Sensors for continuous analyte monitoring, and related methods

ABSTRACT

Sensor devices including dissolvable tissue-piercing tips are provided. The sensor devices can be used in conjunction with dissolvable needles configured for inserting the sensor devices into a host. Hardening agents for strengthening membranes on sensor devices are also provided. Methods of using and fabricating sensor devices are also provided.

TECHNICAL FIELD

The present embodiments relate to systems and methods for measuring ananalyte concentration in a host.

BACKGROUND

Diabetes mellitus is a disorder in which the pancreas cannot createsufficient insulin (Type I or insulin dependent) and/or in which insulinis not effective (Type 2 or non-insulin dependent). In the diabeticstate, the victim suffers from high blood sugar, which may cause anarray of physiological derangements associated with the deterioration ofsmall blood vessels, for example, kidney failure, skin ulcers, orbleeding into the vitreous of the eye. A hypoglycemic reaction (lowblood sugar) may be induced by an inadvertent overdose of insulin, orafter a normal dose of insulin or glucose-lowering agent accompanied byextraordinary exercise or insufficient food intake.

Conventionally, a person with diabetes carries a self-monitoring bloodglucose (SMBG) monitor, which typically requires uncomfortable fingerpricks to obtain blood samples for measurement. Due to the lack ofcomfort and convenience associated with finger pricks, a person withdiabetes normally only measures his or her glucose levels two to fourtimes per day. Unfortunately, time intervals between measurements may bespread far enough apart that the person with diabetes finds out too lateof a hyperglycemic or hypoglycemic condition, sometimes incurringdangerous side effects. It is not only unlikely that a person withdiabetes will take a timely SMBG value, it is also likely that he or shewill not know if his or her blood glucose value is going up (higher) ordown (lower) based on conventional methods. Diabetics thus may beinhibited from making educated insulin therapy decisions.

Another device that some diabetics use to monitor their blood glucose isa continuous analyte sensor. A continuous analyte sensor typicallyincludes a sensor that is placed subcutaneously, transdermally (e.g.,transcutaneously), or intravascularly. The sensor measures theconcentration of a given analyte within the body, and generates a rawsignal that is transmitted to electronics associated with the sensor.The raw signal is converted into an output value that is displayed on adisplay. The output value that results from the conversion of the rawsignal is typically expressed in a form that provides the user withmeaningful information, such as blood glucose expressed in mg/dL.

SUMMARY

The various present embodiments have several features, no single one ofwhich is solely responsible for their desirable attributes. Withoutlimiting the scope of the present embodiments as expressed by the claimsthat follow, their more prominent features now will be discussedbriefly. After considering this discussion, and particularly afterreading the section entitled “Detailed Description,” one will understandhow the features of the present embodiments provide the advantagesdescribed herein.

One aspect of the present embodiments includes the realization that tacksensors include a sharpened tip that remains implanted in the tissuethroughout the usable life of the sensor. Leaving the sharpened tip invivo for an extended period of time may cause trauma to surroundingtissue, leading to scarring and inhibition of wound healing. Some of thepresent embodiments provide solutions to this problem.

In recognition of the foregoing problem, in a first aspect certain ofthe present embodiments comprise a sensor device for measuring ananalyte concentration in a host, the sensor device comprising: a sensorunit comprising a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode, the sensorbody having a blunt tip; a piercing element comprising a material thatrapidly dissolves upon insertion into the host, the piercing elementabutting the sensor tip and being capable of piercing tissue; and amounting unit spaced from the sensor tip and configured to support thesensor device on an exterior surface of the host's skin.

In an embodiment of the first aspect, the piercing element is secured tothe sensor tip.

In an embodiment of the first aspect, the piercing element is adhered tothe sensor tip.

In an embodiment of the first aspect, the piercing element is notsecured to the sensor tip, but is maintained in abutting contacttherewith.

In an embodiment of the first aspect, a sleeve surrounding the sensortip and the piercing element maintains the abutting contact.

In an embodiment of the first aspect, the piercing element comprises acoating that covers at least a portion of the sensor body including thesensor tip.

In an embodiment of the first aspect, the coating comprises a sharpcoating tip.

In an embodiment of the first aspect, the material of the piercingelement comprises a material that suppresses wounding.

In an embodiment of the first aspect, the material of the piercingelement comprises a material that promotes rapid wound healing.

In an embodiment of the first aspect, the material of the piercingelement comprises a material that induces osmotic pressure or oncoticpressure.

In an embodiment of the first aspect, the material of the piercingelement comprises one or more drugs.

In an embodiment of the first aspect, the material of the piercingelement comprises a vascular endothelial growth factor (VEGF).

In an embodiment of the first aspect, the material of the piercingelement comprises at least one of a salt, a metallic salt, a sugar, asynthetic polymer, polylactic acid, polyglycolic acid, or apolyphosphazene.

In an embodiment of the first aspect, the material of the piercingelement biodegrades/dissolves within a first day after insertion intothe host.

In an embodiment of the first aspect, the material of the piercingelement biodegrades/dissolves within three hours after insertion intothe host.

In an embodiment of the first aspect, the piercing element does notextend past the sensor tip in the direction of the mounting unit, orextends only a nominal amount in said direction.

In an embodiment of the first aspect, the piercing element extends pastthe sensor tip in the direction of the mounting unit, but stops short ofthe electrode.

In an embodiment of the first aspect, the mounting unit comprises aguiding portion configured to guide insertion of the sensor unit throughthe host's skin and to support a column strength of the sensor body suchthat the sensor unit is capable of being inserted through the host'sskin without substantial buckling.

In an embodiment of the first aspect, the at least one electrodecomprises a working electrode and a reference electrode.

In an embodiment of the first aspect, the sensor body further comprisesa support member configured to protect the membrane from damage duringinsertion of the sensor unit.

In an embodiment of the first aspect, the at least one electrode is thesupport member.

In an embodiment of the first aspect, the support member is configuredto support at least a portion of the at least one electrode.

In an embodiment of the first aspect, the support member is configuredto substantially surround the at least one electrode.

In an embodiment of the first aspect, the mounting unit comprises asensor electronics unit operatively and detachably connected to thesensor body.

In an embodiment of the first aspect, the sensor electronics unit isconfigured to be located over a sensor insertion site.

Also in recognition of the foregoing problem, in a second aspect certainof the present embodiments comprise a method of making a sensor device,the method comprising: dipping a tip of a sensor into a liquid to form acoating of the liquid on the sensor tip; and withdrawing the sensor tipfrom the liquid while controlling parameters of the withdrawal so thatthe coating forms a sharp point extending from the sensor tip, the sharppoint being capable of piercing tissue.

In an embodiment of the second aspect, the parameters include at leastone of a length (L) of the sensor that is wetted by the liquid, aviscosity of the liquid, and a withdrawal rate.

In an embodiment of the second aspect, L is in the range of 0.1-4 mm.

In an embodiment of the second aspect, L is 2-3 mm.

In an embodiment of the second aspect, the viscosity is below 100 cP.

In an embodiment of the second aspect, the withdrawal rate is 20-30in/sec.

In an embodiment of the second aspect, the method further comprisescuring the coating.

In an embodiment of the second aspect, the curing comprises UV (or heat)cross-linking, irradiating, drying, or heating.

In an embodiment of the second aspect, the method further comprisesusing a tip mold or draw-through fixture that clamps and cures in onestep in order to form a sharp cone shape.

In an embodiment of the second aspect, the method further comprisesapplying a voltage to the coating while it is being cured.

In an embodiment of the second aspect, the method further comprisesheating the coating and drawing it out like glass.

Another aspect of the present embodiments includes the realization thatin some current methods for sensor insertion the sensor is receivedwithin the lumen of an insertion needle. The needle, which has greatercolumn strength than the sensor, bears the frictional forces that occurduring insertion. Once the sensor is in place in the tissue, the needleis removed. The need to remove the needle adds complexity to theinsertion process, including the need to electrically connect the sensorto sensor electronics after insertion. Some of the present embodimentsprovide solutions to this problem.

In recognition of the foregoing problem, in a third aspect certain ofthe present embodiments comprise a sensor device for measuring ananalyte concentration in a host, the sensor device comprising: a sensorunit comprising a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode; and apiercing element comprising a material that rapidly dissolves uponinsertion into the host, the piercing element including a sharp tipcapable of piercing tissue, and a lumen that receives the sensor unit.

In an embodiment of the third aspect, the sensor body has a blunt tip.

In an embodiment of the third aspect, the sensor unit is not secured tothe piercing element.

In an embodiment of the third aspect, the sensor unit is secured to thepiercing element.

In an embodiment of the third aspect, the material of the piercingelement comprises a material that suppresses wounding.

In an embodiment of the third aspect, the material of the piercingelement comprises a material that promotes rapid wound healing.

In an embodiment of the third aspect, the material of the piercingelement comprises a material that induces osmotic pressure or oncoticpressure.

In an embodiment of the third aspect, the material of the piercingelement comprises one or more drugs.

In an embodiment of the third aspect, the material of the piercingelement comprises a vascular endothelial growth factor (VEGF).

In an embodiment of the third aspect, the material of the piercingelement comprises at least one of a salt, a metallic salt, a sugar, asynthetic polymer, polylactic acid, polyglycolic acid, or apolyphosphazene.

In an embodiment of the third aspect, the material of the piercingelement biodegrades/dissolves within a first day after insertion intothe host.

In an embodiment of the third aspect, the material of the piercingelement biodegrades/dissolves within three hours after insertion intothe host.

Another aspect of the present embodiments includes the realization thatthe material of analyte sensor membranes is soft, and tends to peel backas the sensor advances into tissue. This problem is especially acute forsensors that are formed by a process in which they are first coated witha membrane and then sharpened at the tip. This process exposes thesensor body, and leaves a thin coating of the membrane surrounding thesides of the sensor body at the tip. Some of the present embodimentsprovide solutions to this problem.

In recognition of the foregoing problem, in a fourth aspect certain ofthe present embodiments comprise a sensor device for measuring ananalyte concentration in a host, the sensor device comprising: a sensorunit comprising a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode; and amounting unit spaced from the sensor tip and configured to support thesensor device on an exterior surface of the host's skin; wherein themembrane comprises a hardening agent, the hardening agent providingincreased column strength to the sensor unit so that the sensor unit iscapable of being inserted through the host's skin without substantialbuckling.

In an embodiment of the fourth aspect, the hardening agent is integratedwith the membrane.

In an embodiment of the fourth aspect, the membrane covers a tip of thesensor body.

In an embodiment of the fourth aspect, a tip of the sensor body isexposed through the membrane.

In an embodiment of the fourth aspect, the exposed tip of the sensorbody comprises a material that does not react with hydrogen peroxide.

In an embodiment of the fourth aspect, the hardening agent comprisescyanoacrylate.

Also in recognition of the foregoing problem, in a fifth aspect certainof the present embodiments comprise a sensor device for measuring ananalyte concentration in a host, the sensor device comprising: a sensorunit comprising a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode; and amounting unit spaced from the sensor tip and configured to support thesensor device on an exterior surface of the host's skin; wherein themembrane comprises a hardening agent, the hardening agent increasing acolumn strength of the sensor unit and increasing an adhesion of themembrane to the at least one electrode; and wherein the membranecomprising the hardening agent allows analyte permeability.

In an embodiment of the fifth aspect, the hardening agent is suspendedin a matrix.

In an embodiment of the fifth aspect, the membrane covers a tip of thesensor.

In an embodiment of the fifth aspect, a tip of the sensor is exposedthrough the membrane.

In an embodiment of the fifth aspect, the exposed tip of the sensorcomprises a material that does not react with hydrogen peroxide.

In an embodiment of the fifth aspect, the hardening agent comprisescyanoacrylate.

Also in recognition of the foregoing problem, in a sixth aspect certainof the present embodiments comprise a method of making a sensor device,the method comprising: coating a wire with a membrane; cutting thecoated wire to a desired length to thereby form a sensor tip; andexposing the coated wire to a hardening agent such that the membraneabsorbs the hardening agent.

In an embodiment of the sixth aspect, exposing the coated wire comprisesdipping at least the sensor tip in the hardening agent.

In an embodiment of the sixth aspect, certain of the present embodimentsfurther comprise curing the membrane to harden the hardening agent.

In an embodiment of the sixth aspect, certain of the present embodimentsfurther comprise sharpening the sensor tip to form a sharp point capableof piercing tissue.

In an embodiment of the sixth aspect, the sensor tip comprises amaterial that does not react with hydrogen peroxide.

In an embodiment of the sixth aspect, certain of the present embodimentsfurther comprise applying a deadening agent to the sharpened sensor tipto deaden any active surfaces exposed during the sharpening step.

In an embodiment of the sixth aspect, the deadening agent comprisescyanoacrylate or silane.

In an embodiment of the sixth aspect, the deadening agent is appliedusing vapor deposition.

In an embodiment of the sixth aspect, the hardening agent comprisescyanoacrylate.

Also in recognition of the foregoing problem, in a seventh aspectcertain of the present embodiments comprise a method of making a sensordevice, the method comprising: cutting a wire to a desired length tothereby form a sensor tip; sharpening the sensor tip to form a sharppoint capable of piercing tissue; coating the wire, including thesharpened sensor tip, with a membrane; and exposing the coated wire to ahardening agent such that the membrane absorbs the hardening agent.

In an embodiment of the seventh aspect, exposing the coated wirecomprises dipping at least the sensor tip in the hardening agent.

In an embodiment of the seventh aspect, certain of the presentembodiments further comprise curing the membrane to harden the hardeningagent.

In an embodiment of the seventh aspect, the hardening agent comprisescyanoacrylate.

In recognition of any of the problems described herein, in an eighthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host. The sensor device isconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor body comprises a stimulus-responsive materialthat changes at least one material property responsive to a stimulus.

In an embodiment of the eighth aspect, the at least one materialproperty is at least one of hardness, shape, permeability, relativehydrophilicity, modulus of elasticity, or conformation of polymerorientation.

In an embodiment of the eighth aspect, the sensor body is hard ex vivoand soft in vivo.

In an embodiment of the eighth aspect, the stimulus that induces thechange in the at least one material property is at least one oftemperature, hydration, radiation, electrical stimulus, or a magneticfield.

In an embodiment of the eighth aspect, the sensor body is a polymer

In an embodiment of the eighth aspect, the sensor body is polyurethane,polyester, polyamide, polyacrylate, or polyether, or copolymers thereof.

In an embodiment of the eighth aspect, the stimulus-responsive materialis a shape memory metal.

In an embodiment of the eighth aspect, the shape memory metal iscopper-aluminum-nickel (Cu—Al—Ni), nickel-titanium (NiTi),iron-manganese-silicon (Fe—Mn—Si), or copper-zinc-aluminum (Cu—Zn—Al).

In an embodiment of the eighth aspect, the sensor body defines a firstshape prior to insertion into the host's skin.

In an embodiment of the eighth aspect, the sensor body defines amemorized shape, and the sensor body returns to the memorized shapeafter insertion into the host's skin.

In an embodiment of the eighth aspect, the first shape is curved orstraight, and the memorized shape is curved or straight.

In an embodiment of the eighth aspect, when the sensor body returns tothe memorized shape stored spring energy is released from the sensorbody.

In an embodiment of the eighth aspect, the released spring energycreates a whipping action that facilitates piercing the host's skin.

Another aspect of the present embodiments includes the realization thatthe materials used to form the membranes of analyte sensors are oftensoft, and thus tend to delaminate (i.e., peel back and sometimes peeloff) as the sensor advances into skin and/or tissue. This problem isespecially acute for sensors formed by a process in which the sensorsare first coated with a membrane and then sharpened at the tip. Thisprocess exposes the sensor body, and leaves a thin coating of themembrane surrounding the sides of the sensor body at the tip. Some ofthe present embodiments provide solutions to this problem, including howto form the tip after applying the membrane, without damaging the tip,and while still maintaining the integrity of the tip.

In recognition of the foregoing problem, in a ninth aspect certain ofthe present embodiments comprise a method of making a sensor deviceconfigured for implantation in a host without use of an inserter. Themethod comprises forming a piercing tip on a sensor unit, the sensorunit including a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode. The membraneis applied to the sensor unit prior to forming the piercing tip on thesensor unit.

In an embodiment of the ninth aspect, the method further comprisesapplying the membrane to the sensor unit.

In an embodiment of the ninth aspect, forming the piercing tip comprisesforming an annular channel about a circumference of a wire that iscoated with the membrane.

In an embodiment of the ninth aspect, the annular channel extendsthrough the membrane and partially into the wire

In an embodiment of the ninth aspect, the method further comprisesapplying tension to the coated wire.

In an embodiment of the ninth aspect, the tension induces strain in thewire proximate the annular channel, causing the wire to neck andfracture.

In an embodiment of the ninth aspect, the necking forms the piercing tipon the sensor body.

In an embodiment of the ninth aspect, the method further comprisescovering the piercing tip with a protective outer layer.

In an embodiment of the ninth aspect, forming the piercing tip comprisesselectively removing portions of a membrane coating from wire stock.

In an embodiment of the ninth aspect, the wire stock is wound on a reel.

In an embodiment of the ninth aspect, the method further comprisessingulating the wire stock at spaced locations to form a plurality ofmembrane-coated sensor wires.

In an embodiment of the ninth aspect, forming the piercing tip comprisesexposing a distal end surface of the sensor body.

In an embodiment of the ninth aspect, the method further comprisesapplying a coating over the distal end of the sensor body.

In an embodiment of the ninth aspect, the coating renders the exposeddistal end surface of the sensor body non-electroactive.

In an embodiment of the ninth aspect, forming the piercing tip comprisesapplying an end cap to a distal end of a membrane-coated sensor wire.

In an embodiment of the ninth aspect, the end cap includes the piercingtip.

In an embodiment of the ninth aspect, forming the piercing tip comprisesapplying a plurality of membrane layers to the sensor body.

In an embodiment of the ninth aspect, forming the piercing tip furthercomprises applying a rigid coating at a distal end of the sensor bodyover the plurality of membrane layers.

In an embodiment of the ninth aspect, forming the piercing tip furthercomprises shaping the rigid coating to produce the piercing tip.

In an embodiment of the ninth aspect, the method further comprisesapplying the membrane to the sensor body.

In an embodiment of the ninth aspect, the method further comprisesapplying the piercing tip to a distal end of the sensor body.

In an embodiment of the ninth aspect, the piercing tip is secured to thedistal end of the sensor body by mechanical crimping, press fitting,welding, shrink tubing, or heating.

In an embodiment of the ninth aspect, the method further comprisesapplying a retractable introducer sheath around the sensor body.

In an embodiment of the ninth aspect, forming the piercing tip comprisesapplying the piercing tip to a distal end of the sensor body over themembrane.

In an embodiment of the ninth aspect, the piercing tip comprises amaterial that is biodegradable and/or bioabsorbable.

In an embodiment of the ninth aspect, the piercing tip materialcomprises polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), ormaltose.

In an embodiment of the ninth aspect, applying the piercing tip to adistal end of the sensor body over the membrane comprises casting thepiercing tip onto the distal end of the sensor body and over themembrane using a mold.

In an embodiment of the ninth aspect, applying the piercing tip to adistal end of the sensor body over the membrane comprises injectionmolding or insert molding.

In an embodiment of the ninth aspect, applying the piercing tip to adistal end of the sensor body over the membrane comprises inserting adistal end of the sensor body into an open proximal end of the piercingtip.

In an embodiment of the ninth aspect, the method further comprisescrimping the proximal end of the piercing tip.

In an embodiment of the ninth aspect, applying the piercing tip to adistal end of the sensor body over the membrane comprises overmoldingthe piercing tip to the distal end of the sensor body and over themembrane.

Another aspect of the present embodiments includes the realization thatapplying a membrane to a sharp sensor tip presents challenges. Forexample, the sharp tip can breach the membrane and/or cause the membraneto delaminate, particularly when the sensor is subjected to frictionalforces during the process of sensor insertion. Also, applying a membraneto a sharp sensor tip may dull the tip, rendering the tip less effectivefor direct press insertion of the sensor. Some of the presentembodiments provide solutions to these problems, including how to applythe membrane to a sharp tip, without damaging the tip, and whilemaintaining the integrity of the tip.

In recognition of the foregoing problem, in a tenth aspect certain ofthe present embodiments comprise a method of making a sensor deviceconfigured for implantation in a host without use of an inserter. Themethod comprises forming a piercing tip on a sensor unit, the sensorunit including a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode. The piercingtip is formed on the sensor unit prior to applying the membrane to thesensor unit.

In an embodiment of the tenth aspect, forming the piercing tip comprisesdipping the sensor body in a membrane solution to form the membrane onthe sensor body.

In an embodiment of the tenth aspect, forming the piercing tip furthercomprises, after the membrane solution dries, removing a portion of themembrane at a distal end of the sensor body to expose the distal end ofthe sensor body.

In an embodiment of the tenth aspect, removing the portion of themembrane at the distal end of the sensor body comprises laser ablation,electropolishing, bead blasting, dry ice blasting, or burning.

In an embodiment of the tenth aspect, the method further comprisesapplying a protective layer over the distal end of the sensor body.

In an embodiment of the tenth aspect, forming the piercing tip furthercomprises removing a portion of the membrane solution, prior to themembrane solution drying, at a distal end of the sensor body.

In an embodiment of the tenth aspect, removing the portion of themembrane solution comprises blotting or wiping the distal end of thesensor body.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the sensor body and the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesapplying a coating to the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesapplying a retractable introducer sheath around the sensor body.

In an embodiment of the tenth aspect, an outer diameter of theintroducer sheath is substantially equal to, or less than, a diameter ofthe piercing tip at a proximal end thereof.

In an embodiment of the tenth aspect, the sensor body includes a coreand an outer layer.

In an embodiment of the tenth aspect, the membrane is applied over theouter layer, but not over the core.

In an embodiment of the tenth aspect, the core and the outer layercomprise different materials.

In an embodiment of the tenth aspect, the core comprises a material thatrepels the membrane.

In an embodiment of the tenth aspect, the material of the core has a lowsurface energy.

In an embodiment of the tenth aspect, the material of the core isnon-wetting.

In an embodiment of the tenth aspect, forming the piercing tip compriseselectrochemical grinding.

In an embodiment of the tenth aspect, the membrane comprises a pluralityof layers.

In an embodiment of the tenth aspect, a thickness of each layer is in arange from about 0.5 microns to about 10 microns.

In an embodiment of the tenth aspect, a thickness of at least one of thelayers is less than a thickness of at least another one of the layers.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the sensor body and the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesremoving the membrane from the piercing tip, but not from the sensorbody.

In an embodiment of the tenth aspect, removing the membrane from thepiercing tip comprises chemical etching, laser ablation, or mechanicalstripping.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the sensor body and the piercing tip by dippingin a membrane solution.

In an embodiment of the tenth aspect, the method further comprisesdipping the piercing tip in a solvent to dissolve the membrane andsubstantially remove the membrane from the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesdipping the piercing tip in a release agent that prevents the membranefrom adhering to the piercing tip.

In an embodiment of the tenth aspect, forming the piercing tip comprisescoating the piercing tip with a sacrificial material.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the sensor body and the piercing tip.

In an embodiment of the tenth aspect, the method further comprisestreating the piercing tip to break down the sacrificial layer and removethe membrane from the piercing tip.

In an embodiment of the tenth aspect, the sacrificial material is lightsensitive, heat sensitive, or soluble, and treating the piercing tipcomprises applying light, applying heat, or applying a solvent.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the piercing tip by dipping the piercing tip ina membrane solution with the piercing tip pointed downward, andsubsequently inverting the sensor unit, before the solution dries, suchthat piercing tip is pointed upward.

In an embodiment of the tenth aspect, the method further comprisesapplying the membrane to the sensor body by dipping the sensor body in amembrane solution with the piercing tip pointed upward, such that thesensor body is only partially submerged in the membrane solution and themembrane solution never contacts the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesremoving an annular band of material from the sensor body just proximalof the piercing tip to form an annular channel, wherein a distal end ofthe channel defines an edge.

In an embodiment of the tenth aspect, the method further comprisesdipping the sensor body and the piercing tip in a membrane solution.

In an embodiment of the tenth aspect, the edge causes a liquid meniscusof the membrane solution to break off, thereby leaving the piercing tipuncovered by the membrane.

In an embodiment of the tenth aspect, the sensor body includes a coreand an outer layer.

In an embodiment of the tenth aspect, the method further comprisesremoving a first portion of the outer layer and a second portion of theouter layer to expose the core.

In an embodiment of the tenth aspect, the first portion of the outerlayer is located adjacent the piercing tip, and the second portion ofthe outer layer is located proximal of the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesremoving a portion of the core to form the piercing tip.

In an embodiment of the tenth aspect, the method further comprisesattaching a cap over the piercing tip.

In an embodiment of the tenth aspect, the attached cap includes a sharpdistal end.

In an embodiment of the tenth aspect, the attached cap comprises anabsorbable material such that the cap is absorbed into a body of thehost after the sensor body is inserted into skin and/or tissue of thehost.

In an embodiment of the tenth aspect, the sensor body includes a planar,flexible printed circuit board (PCB) embedded in an outer core.

In an embodiment of the tenth aspect, the method further comprisesremoving a section of the outer core proximal of the piercing tip toform a window.

In an embodiment of the tenth aspect, removing the section of the outercore comprises laser ablation.

In an embodiment of the tenth aspect, an outer surface of the PCB in anarea of the window includes a platinum layer that resists the laserablation.

In an embodiment of the tenth aspect, the method further comprisesdipping the sensor body in a membrane solution to form the membranewithin the window.

In an embodiment of the tenth aspect, the sensor body includes a thin,flat microelectromechanical systems (MEMS) substrate.

In an embodiment of the tenth aspect, the substrate includes thepiercing tip.

In an embodiment of the tenth aspect, the method further comprisesforming the membrane on the substrate.

Another aspect of the present embodiments includes the realization thatforming a sharp distal tip on a sensor presents challenges, such ascontaminating the membrane surface and/or damaging the membrane so thatit cannot perform its proper function. Contamination of the membrane canalter membrane properties such as diffusion. For example, a contaminantmay reduce the permeability characteristics (e.g., permselectivity) ofthe membrane. Damage to the membrane can also affect the functionalityof the sensor. For example, if membrane removal extends beyond thedistal tip to a portion intended to cover the electroactive surface thatforms an electrode, the sensor can become defective, as diffusionproperties of the sensor become substantially altered and uncontrolled.On the other hand, if excess membrane material is present at the distaltip of the sensor, the distal tip of the sensor may become dull, suchthat it becomes less effective for piercing skin and/or tissue. Some ofthe present embodiments provide solutions to these problems, includinghow to form a sharp distal tip by removing material from the tip and howto form a sharp distal tip by adding material to the tip. Another aspectof the present embodiments includes the realization that a piercing tipcan be formed on sensors during a step of singulating a sensor wire intoindividual sensors. For example, singulating processes may include,without limitation, mechanical pressing, hot pressing, laser ablation,extruding, milling, etc. By forming a piercing tip during singulation, asharp distal tip can be formed prior to applying the membrane to thesensor, thereby avoiding cross-contamination and damaging the delicatemembrane with a subsequent tip-forming step.

In recognition of the foregoing problems, in a eleventh aspect certainof the present embodiments comprise a method of making a sensor deviceconfigured for implantation in a host without use of an inserter. Themethod comprises forming a piercing tip on a sensor unit, the sensorunit including a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode. Forming thepiercing tip comprises removing material from the sensor body.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises singulating wire stock while exposing the wire stock tocyanoacrylate vapor.

In an embodiment of the eleventh aspect, the method includesreel-to-reel continuous processing.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises dipping a distal end of the sensor body.

In an embodiment of the eleventh aspect, dipping the distal end of thesensor body comprises dipping in an etchant or a polishing solution.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises electropolishing.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises moving the sensor body relative to an abrasive surface withthe sensor body forming an angle Θ relative to the abrasive surface.

In an embodiment of the eleventh aspect, Θ is between 0° and 90°.

In an embodiment of the eleventh aspect, Θ is about 5°, or about 10°, orabout 15°.

In an embodiment of the eleventh aspect, the sensor body is held withina support fixture that is moved relative to the abrasive surface.

In an embodiment of the eleventh aspect, the sensor body includes aninner core and an outer layer, and forming the piercing tip comprisesremoving a portion of the outer layer at a distal end of the sensor bodyto expose a portion of the inner core.

In an embodiment of the eleventh aspect, removing the portion of theouter layer comprises mechanical stripping, laser ablation, beadblasting, abrasion, or chemical etching.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises applying tension to a sensor wire along a longitudinal axis ofthe sensor wire.

In an embodiment of the eleventh aspect, the applied tension causes thesensor wire to neck in an intermediate region.

In an embodiment of the eleventh aspect, the applied tension furthercauses the sensor wire to fail in the intermediate region.

In an embodiment of the eleventh aspect, the method further comprisesapplying heat to the sensor wire in the intermediate region, wherein theheat is applied simultaneously with the tension.

In an embodiment of the eleventh aspect, the heat is applied with aresistive heating element.

In an embodiment of the eleventh aspect, forming the piercing tipcomprises positioning a sensor wire between opposing cutting blades andsingulating the sensor wire into at least two pieces.

In an embodiment of the eleventh aspect, a cutting edge defined byconverging surfaces of one of the cutting blades defines an anglebetween 30 degrees and 145 degrees.

In an embodiment of the eleventh aspect, the angle is not a right angle.

Also in recognition of the foregoing problems, in a twelfth aspectcertain of the present embodiments comprise a method of making a sensordevice configured for implantation in a host without use of an inserter.The method comprises forming a piercing tip on a sensor unit, the sensorunit including a sensor body, at least one electrode, and a membranecovering at least a portion of the at least one electrode. Forming thepiercing tip comprises adding material to the sensor body.

In an embodiment of the twelfth aspect, forming the piercing tipcomprises dipping the sensor body in a bath of a polymer material.

In an embodiment of the twelfth aspect, the method further comprisesremoving the sensor body from the bath and applying a voltage across thepolymer material, thereby causing the polymer material to elongate andform the piercing tip.

In an embodiment of the twelfth aspect, the method compriseselectrospinning.

In an embodiment of the twelfth aspect, forming the piercing tipcomprises dipping the sensor body in a bath and withdrawing the sensorbody from the bath, and as the sensor body is withdrawn a dip coating onthe sensor body cures to form the piercing tip.

In recognition of any of the problems described herein, in a thirteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a conductive core wire. The sensor devicefurther comprises a nonconductive jacket disposed over at least aportion of the core wire. The sensor device further comprises at leastone electrode disposed over the jacket and electrically connected to thecore wire. The at least one electrode is formed by printing.

In an embodiment of the thirteenth aspect, the at least one electrodecomprises a first electrode, a second electrode, and a third electrode,and the electrodes are axially spaced along the sensor device.

In an embodiment of the thirteenth aspect, the second electrode does notextend around the entire circumference of the jacket.

In an embodiment of the thirteenth aspect, the sensor device furthercomprises a conductive trace extending along the jacket between thefirst and third electrodes.

In an embodiment of the thirteenth aspect, the sensor device furthercomprises an insulator overlying at least a portion of the conductivetrace.

In an embodiment of the thirteenth aspect, a distal end of the sensordevice includes a piercing tip.

In an embodiment of the thirteenth aspect, a distal end of the sensordevice is non-electroactive.

In recognition of any of the problems described herein, in a fourteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a nonconductive core wire. The sensor devicefurther comprises at least one electrode disposed over the core wire.The sensor device further comprises at least one conductive traceextending from the at least one electrode along the core wire. The atleast one electrode is formed by printing.

In an embodiment of the fourteenth aspect, the at least one electrodecomprises a first electrode, a second electrode, and a third electrode,and the electrodes are axially spaced along the sensor device.

In an embodiment of the fourteenth aspect, the first and secondelectrodes do not extend around the entire circumference of the corewire.

In an embodiment of the fourteenth aspect, a distal end of the sensordevice includes a piercing tip.

In an embodiment of the fourteenth aspect, the at least one electrode isprinted on the core wire with a platinum paste.

In recognition of any of the problems described herein, in a fifteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor body shaped as a flat sheet rolled intoa cylinder.

In an embodiment of the fifteenth aspect, the cylinder includes anoverlap region where opposite edges of the flat sheet converge.

In an embodiment of the fifteenth aspect, overlapping portions of theopposite edges are secured to one another.

In an embodiment of the fifteenth aspect, the overlapping portions aresecured to one another with an adhesive.

In an embodiment of the fifteenth aspect, the adhesive dissolves afterthe sensor device is implanted in the host.

In an embodiment of the fifteenth aspect, upon dissolution of theadhesive, the rolled sensor body unrolls to reassume its flat shape.

In recognition of any of the problems described herein, in a sixteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor device further comprises a retractableintroducer sheath configured to cover at least a portion of the membraneduring insertion of the sensor device.

In an embodiment of the sixteenth aspect, a proximal end of the tissuepiercing element has a diameter greater than a diameter of the sensorbody.

In an embodiment of the sixteenth aspect, a diameter of the introducersheath is substantially equal to or less than the diameter of theproximal end of the tissue piercing element.

In recognition of any of the problems described herein, in a seventeenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor body includes a cross-section that defines atleast one trough that extends along a length of the sensor body.

In an embodiment of the seventeenth aspect, the cross-section of thesensor body defines a plus sign with four evenly spaced troughs.

In an embodiment of the seventeenth aspect, the cross-section of thesensor body defines a circle with a single trough.

In an embodiment of the seventeenth aspect, the at least one electrodeis located in the at least one trough.

In an embodiment of the seventeenth aspect, the at least one electrodeand the at least one membrane are flush with or recessed beneath anouter perimeter of the sensor body.

In recognition of any of the problems described herein, in an eighteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor device further comprises a retractableintroducer sheath configured to cover at least a portion of the membraneduring insertion of the sensor device.

In recognition of any of the problems described herein, in a nineteenthaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor device further comprises at least one throughhole extending through the sensor body.

In an embodiment of the nineteenth aspect, the membrane is disposedwithin the at least one through hole.

In recognition of any of the problems described herein, in a twentiethaspect certain of the present embodiments comprise a sensor device formeasuring an analyte concentration in a host, the sensor device beingconfigured for implantation in the host without use of an inserter. Thesensor device comprises a sensor unit comprising a sensor body, at leastone electrode, and a membrane covering at least a portion of the atleast one electrode. The sensor device further comprises a piercingelement at a distal end of the sensor unit, the piercing element beingconfigured for piercing skin and/or tissue of the host. The sensordevice further comprises a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin. The sensor body includes a plurality of depressions.

In an embodiment of the twentieth aspect, the membrane is disposedwithin at least one of the depressions.

In an embodiment of the twentieth aspect, the membrane is flush with anouter surface of the sensor body, or recessed beneath the outer surfaceof the sensor body.

In an embodiment of the twentieth aspect, the depressions are randomlyarranged.

In recognition of any of the problems described herein, in atwenty-first aspect certain of the present embodiments comprise a sensordevice for measuring an analyte concentration in a host, the sensordevice being configured for implantation in the host without use of aninserter. The sensor device comprises a sensor unit comprising a sensorbody, at least one electrode, and a membrane covering at least a portionof the at least one electrode. The sensor device further comprises apiercing element at a distal end of the sensor unit, the piercingelement being configured for piercing skin and/or tissue of the host.The sensor device further comprises a mounting unit spaced from thesensor tip and configured to support the sensor device on an exteriorsurface of the host's skin. The sensor device further comprises aplurality of axially spaced depressions in the sensor body.

In an embodiment of the twenty-first aspect, the membrane is disposedwithin the depressions.

In an embodiment of the twenty-first aspect, the sensor device furthercomprises an outer layer of a material that is permeable to one or moreselected analytes.

In recognition of any of the problems described herein, in atwenty-second aspect certain of the present embodiments comprise asensor device for measuring an analyte concentration in a host, thesensor device being configured for implantation in the host without useof an inserter. The sensor device comprises a sensor unit comprising asensor body, at least one electrode, and a membrane covering at least aportion of the at least one electrode. The sensor device furthercomprises a piercing element at a distal end of the sensor unit, thepiercing element being configured for piercing skin and/or tissue of thehost. The sensor device further comprises a mounting unit spaced fromthe sensor tip and configured to support the sensor device on anexterior surface of the host's skin. The sensor device further comprisesa protective outer layer disposed over the sensor body and the membrane.

In an embodiment of the twenty-second aspect, the protective outer layercomprises a material that dissolves upon insertion into skin and/ortissue of the host.

In an embodiment of the twenty-second aspect, the material of theprotective outer layer comprises polyvinyl-pyrrolidone (PVP).

In recognition of any of the problems described herein, in atwenty-third aspect certain of the present embodiments comprise a sensordevice for measuring an analyte concentration in a host, the sensordevice being configured for implantation in the host without use of aninserter. The sensor device comprises a sensor unit comprising a sensorbody, at least one electrode, and a membrane covering at least a portionof the at least one electrode. The sensor device further comprises apiercing element at a distal end of the sensor unit, the piercingelement being configured for piercing skin and/or tissue of the host.The sensor device further comprises a mounting unit spaced from thesensor tip and configured to support the sensor device on an exteriorsurface of the host's skin. The sensor device further comprises an outerlayer of a rigid material.

In an embodiment of the twenty-third aspect, the outer layer coverssubstantially all of the sensor body, but includes at least one window.

In an embodiment of the twenty-third aspect, the window is located overthe at least one electrode such that the at least one electrode isexposed for contact with tissue and/or bodily fluids of the host.

In an embodiment of the twenty-third aspect, the outer layer comprisescyanoacrylate.

In recognition of any of the problems described herein, in atwenty-fourth aspect certain of the present embodiments comprise asensor device for measuring an analyte concentration in a host, thesensor device being configured for implantation in the host without useof an inserter. The sensor device comprises a sensor unit comprising asensor body, at least one electrode, and a membrane covering at least aportion of the at least one electrode. The sensor device furthercomprises a piercing element at a distal end of the sensor unit, thepiercing element being configured for piercing skin and/or tissue of thehost. The sensor device further comprises a mounting unit spaced fromthe sensor tip and configured to support the sensor device on anexterior surface of the host's skin. The sensor body comprises aconductive wire and an outer coating disposed over the wire, and theouter coating has a greater thickness than the wire.

In an embodiment of the twenty-fourth aspect, the outer coating includesat least one window corresponding to a location of the at least oneelectrode.

In an embodiment of the twenty-fourth aspect, the membrane is disposedwithin the window.

In an embodiment of the twenty-fourth aspect, the membrane is recessedbeneath an outer surface of the outer coating.

In an embodiment of the twenty-fourth aspect, the sensor device furthercomprises a highly permeable outer layer.

In an embodiment of the twenty-fourth aspect, the outer layer comprisesa hydrogel.

In recognition of any of the problems described herein, in atwenty-fifth aspect certain of the present embodiments comprise a sensordevice for measuring an analyte concentration in a host, the sensordevice being configured for implantation in the host without use of aninserter. The sensor device comprises a sensor unit comprising a sensorbody, at least one electrode, and a membrane covering at least a portionof the at least one electrode. The sensor device further comprises apiercing element at a distal end of the sensor unit, the piercingelement being configured for piercing skin and/or tissue of the host.The sensor device further comprises a mounting unit spaced from thesensor tip and configured to support the sensor device on an exteriorsurface of the host's skin. Membrane is applied to the sensor body byprinting.

In an embodiment of the twenty-fifth aspect, the sensor body comprisespolytetrafluoroethylene (PTFE).

BRIEF DESCRIPTION OF THE DRAWINGS

The various present embodiments now will be discussed in detail with anemphasis on highlighting the advantageous features. These embodimentsdepict the novel and non-obvious sensors for continuous analytemonitoring, and related methods, shown in the accompanying drawings,which are for illustrative purposes only. The figures are notnecessarily drawn to scale, and they are provided merely to illustratethe present embodiments. These drawings include the following figures,in which like numerals indicate like parts:

FIG. 1 is a schematic cross-sectional view of a continuous analytesensor according to the present embodiments;

FIGS. 2A-2H are schematic side views of example shapes oftissue-piercing tips for a continuous analyte sensor according to thepresent embodiments;

FIGS. 3A-3D are top perspective views of additional continuous analytesensors according to the present embodiments;

FIG. 4 is a continuous analyte sensor according to the presentembodiments;

FIG. 5 is a front perspective view of a system for inserting acontinuous analyte sensor into a host according to the presentembodiments;

FIG. 6 is a front perspective view of another system for inserting acontinuous analyte sensor into a host according to the presentembodiments;

FIG. 7 is a continuous analyte sensor according to the presentembodiments;

FIG. 8 is a continuous analyte sensor according to the presentembodiments;

FIG. 9 is a continuous analyte sensor according to the presentembodiments;

FIG. 10 is a continuous analyte sensor according to the presentembodiments;

FIG. 11 is a schematic front elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 12 is a schematic rear elevation view of the sensor of FIG. 11;

FIG. 13 is a schematic front elevation view of another sensor configuredfor direct press insertion according to the present embodiments;

FIG. 14 is a schematic rear elevation view of the sensor of FIG. 13;

FIG. 15 is a schematic side perspective view of another sensorconfigured for direct press insertion according to the presentembodiments;

FIG. 16 is a schematic end perspective view of another sensor configuredfor direct press insertion according to the present embodiments;

FIG. 17 is a schematic end perspective view of the sensor of FIG. 16after the sensor has been rolled into a cylinder;

FIG. 18 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 19 is a schematic side elevation view of the sensor of FIG. 18after the retractable introducer sheath has been retracted;

FIG. 20 is a schematic distal end perspective view of a sensorconfigured for direct press insertion according to the presentembodiments;

FIG. 21 is a schematic distal end elevation view of the sensor of FIG.20;

FIG. 22 is a schematic distal end elevation view of a sensor configuredfor direct press insertion according to the present embodiments;

FIG. 23 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 24 is a schematic side perspective view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 25 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 26 is a schematic side cross-sectional view of a sensor configuredfor direct press insertion according to the present embodiments;

FIG. 27 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 28 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 29 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIG. 30 is a schematic side elevation view of a sensor configured fordirect press insertion according to the present embodiments;

FIGS. 30A and 30B are schematic side elevation views of a process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIGS. 31-33 are schematic side elevation views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIG. 34 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIGS. 35-37 are schematic cross-sectional side elevation views ofanother process for making a sensor configured for direct pressinsertion according to the present embodiments;

FIGS. 38 and 39 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIGS. 40 and 41 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIGS. 42 and 43 are schematic cross-sectional side elevation views ofanother process for making a sensor configured for direct pressinsertion according to the present embodiments;

FIGS. 44 and 45 are schematic cross-sectional side elevation views ofanother process for making a sensor configured for direct pressinsertion according to the present embodiments;

FIGS. 46-48 are schematic side elevation views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIGS. 49-51 are schematic side elevation views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIG. 52 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 52A is a schematic cross-sectional side elevation view of anotherprocess for making a sensor configured for direct press insertionaccording to the present embodiments;

FIG. 53 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 54 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 54A is a detail view of the portion of FIG. 54 indicated by thecircle 54A-54A in FIG. 54;

FIGS. 55 and 56 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIGS. 57 and 58 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIG. 59 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 60 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIGS. 61 and 62 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIG. 63 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 64 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIGS. 65-67 are schematic side elevation views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIG. 68 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 69 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 70 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 71 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIGS. 72 and 73 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIGS. 74 and 75 are schematic side elevation views of another processfor making a sensor configured for direct press insertion according tothe present embodiments;

FIG. 76 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 76A is a schematic end elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 76B-76D are cross-sectional schematic end views of the process formaking a sensor configured for direct press insertion according to FIG.76A;

FIG. 77 is a schematic tip plan view of another process for making asensor configured for direct press insertion according to the presentembodiments;

FIG. 78 is schematic side elevation view of the process of FIG. 77;

FIG. 79 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIGS. 80 and 81 are schematic top plan views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments;

FIG. 82 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments;

FIG. 83 is a schematic side elevation view of another process for makinga sensor configured for direct press insertion according to the presentembodiments; and

FIGS. 84-86 are schematic side elevation views of another process formaking a sensor configured for direct press insertion according to thepresent embodiments.

DETAILED DESCRIPTION

The following detailed description describes the present embodimentswith reference to the drawings. In the drawings, reference numbers labelelements of the present embodiments. These reference numbers arereproduced below in connection with the discussion of the correspondingdrawing features.

The drawings and their descriptions may indicate sizes, shapes andconfigurations of the various components. Such depictions anddescriptions should not be interpreted as limiting. Alternative sizes,shapes and configurations are also contemplated as within the scope ofthe present embodiments. Also, the drawings, and their writtendescriptions, indicate that certain components of the apparatus areformed integrally, and certain other components are formed as separatepieces. Components shown and described herein as being formed integrallymay in alternative embodiments be formed as separate pieces. Further,components shown and described herein as being formed as separate piecesmay in alternative embodiments be formed integrally. As used herein theterm integral describes a single unitary piece.

Overview

The embodiments described herein provide various mechanisms for directlyinserting a transcutaneous sensor into a host without the use of aseparate applicator, i.e., other than the sensor device itself. Directpress insertion of a transcutaneous sensor (e.g., an electrode) having awire-like geometry, especially a fine wire, may be technicallychallenging because of buckling risks associated with the sensor. Directpress insertion of a sensor also presents challenges relating to damageduring the insertion process to the membrane disposed on the sensor.Without membrane protection, the membrane may be stripped off the sensoror be mechanically damaged during the insertion process. It is alsodesirable to avoid having exposed metal (or other electricallyconductive material) at the tip of the sensor, because exposed metal maybe electroactive and add background signal (noise) and/or cause thesensitivity of the sensor to vary. The embodiments described herein aredesigned to overcome the aforementioned challenges by providingminiaturized sensor devices capable of providing structural support(e.g., in the form of mechanical/structural properties such as columnstrength) for direct insertion of a transcutaneous sensor, and capableof protecting the membrane from damage during the insertion process.

FIG. 1 illustrates a schematic side view of one embodiment of atranscutaneous sensor device 100 configured to continuously measureanalyte concentration (e.g., glucose concentration) in a host to providea data stream representative of the host's analyte concentration, inaccordance with the present embodiments. Sensors such as the oneillustrated in FIG. 1 are sometimes referred to as “tack” sensors, dueto their resemblance to a thumbtack.

In the particular embodiment illustrated in FIG. 1, the sensor device100 comprises an in vivo portion 102 (also referred to as a sensor unit)configured for insertion under the host's skin 104, and an ex vivoportion 106 configured to remain above the host's skin surface aftersensor insertion. The in vivo portion 102 comprises a tissue-piercingelement 108 configured for piercing the host's skin 104, and a sensorbody 110. The sensor body 110 comprises a support member 112 includingone or more electrodes, and a membrane 114 disposed over at least aportion of the support member 112. The support member 112 may also bereferred to as a sensor body 112, and the two terms are usedinterchangeably herein.

The ex vivo portion 106 comprises a mounting unit 116 that may include asensor electronics unit (not shown) embedded or detachably securedtherein, or alternatively may be configured to operably connect to aseparate sensor electronics unit. Further details regarding the sensordevice 100 and its components may be found in U.S. Patent ApplicationPublication No. 2011/0077490, the disclosure of which is incorporatedherein in its entirety.

Tissue-Piercing Element

The tissue-piercing element 108 of the sensor device 100 is configuredto pierce the host's skin 104, and to open and define a passage forinsertion of the sensor body 110 into a tissue of the host. In someembodiments, the tissue-piercing element 108 may be integral with thesupport member 112. In other embodiments, the tissue-piercing element108 may be a discrete component. In such embodiments, thetissue-piercing element 108 may be secured to the support member 112,such as with an adhesive. Alternatively, the tissue-piercing element 108may merely abut a blunt distal face of the support member 112 and/or themembrane 114. In such embodiments, an outer sleeve or band (not shown)may encircle a junction of the tissue-piercing element 108 and thesupport member 112/membrane 114.

The skin generally comprises multiple layers, including the epidermis,dermis, and subcutaneous layers. The epidermis comprises a number oflayers within its structure including the stratum corneum, which is theoutermost layer and is generally from about 10 to 20 microns thick, andthe stratum germinativum, which is the deepest layer of the epidermis.While the epidermis generally does not contain blood vessels, itexchanges metabolites by diffusion to and from the dermis. While notwishing to be bound by theory, it is believed that because the stratumgerminativum is supported by vascularization for survival, theinterstitial fluid at the stratum germinativum sufficiently represents ahost's analyte (e.g., glucose) levels. Beneath the epidermis is thedermis, which is from about 1 mm to about 3 mm thick and contains bloodvessels, lymphatics, and nerves. The subcutaneous layer lies underneaththe dermis and is mostly comprised of fat. The subcutaneous layer servesto insulate the body from temperature extremes. It also containsconnective tissue and a small amount of blood vessels.

In some embodiments, the in vivo portion 102 of the sensor device 100may have a length long enough to allow for at least a portion of thesensor body 110 to reside within the stratum germinativum. This may bedesirable in some instances because the epidermis does not contain asubstantial number of blood vessels or nerve endings. Thus, sensorinsertion may be relatively painless, and the host may not experiencemuch bleeding or discomfort from the insertion. In some of theseembodiments, the in vivo portion 102 of the sensor device 100 may have alength of from about 0.1 mm to about 1.5 mm, or from about 0.2 mm toabout 0.5 mm. In other embodiments, the in vivo portion 102 of thesensor device 100 may have a length that allows for at least a portionof the sensor body 110 to reside in the dermis layer. This may bedesirable in some instances because the dermis is well vascularized, ascompared to the subcutaneous layer, and thus may provide sufficientanalytes (e.g., glucose) for measurement and reduce measurement lagsassociated with changes of analyte concentrations of a host, such asthose that occur after meals. The metabolically active tissue near theouter dermis (and also the stratum germinativum) provides rapidequilibrium of the interstitial fluid with blood. In some of theseembodiments, the in vivo portion 102 of the sensor device may have alength of from about 1 mm to about 7 mm, or from about 2 mm to about 6mm. In still other embodiments, the in vivo portion 102 of the sensordevice 100 may have a length that allows for at least a portion of thesensor body 110 to reside in the subcutaneous layer. While not wishingto be bound by theory, it is believed that because the subcutaneouslayer serves to insulate the body from temperature extremes, thesubcutaneous layer may reduce variations of analyte concentrationreadings associated with temperature fluctuations. In some of theseembodiments, the in vivo portion 102 of the sensor device may have alength of from about 3 mm to about 10 mm, or from about 5 mm to about 7mm.

The tissue-piercing element may have any of a variety of geometricshapes and dimensions, including ones that minimize tissue trauma andreduce the force required for skin penetration. For example, in someembodiments, the tissue-piercing element may comprise a substantiallyconically-shaped distal tip, as illustrated in FIG. 1, such that thecross-sectional dimensions (e.g., diameter) of the tissue-piercingelement tapers to a point 118 at the distal end of the tip, therebyproviding a sharpened leading edge configured to facilitate skinpenetration. As illustrated in FIG. 2B, in other embodiments, the distaltip of the tissue-piercing element may be beveled with a bevel angle α,such as, for example, an angle of from about 5° to about 66°, or fromabout 10° to about 55°, or from about 40° to about 50°. In furtherembodiments, one or more surfaces of the tip may be curved, such asillustrated in FIGS. 2C-2H and 3D, so as to facilitate skin penetrationwhen the sensor device is pushed downwards. In some embodiments, acurved surface may be advantageous because it provides thetissue-piercing element with a greater cutting surface area than astraight surface, and thus provides a smoother and more controlledinsertion of the sensor unit through the skin. Also, a tissue-piercingelement with a curved surface may cause less trauma to the piercedtissue than one with a straight surface.

The tissue-piercing element of the sensor device is designed to haveappropriate flexibility and hardness and sufficient column strength toallow it to remain intact and to prevent it from substantial bucklingduring insertion of the in vivo portion of the sensor device through theskin of the host. Any of a variety of biocompatible materials havingthese characteristics may be used to form the tissue-piercing element,including, but not limited to, metals, ceramics, semiconductors,organics, polymers, composites, and combinations or mixtures thereof.Metals that may be used include stainless steel (e.g., 18-8 surgicalsteel), nitinol, gold, silver, nickel, titanium, tantalum, palladium,gold, and combinations or alloys thereof, for example. Polymers that maybe used include polycarbonate, polymethacrylic acid, ethylenevinylacetate, polytetrafluorethylene (TEFLON®), and polyesters, for example.In some embodiments, the tissue-piercing element may serve as areference electrode and comprise a conductive material, such as asilver-containing material, for example. In certain embodiments, thetissue-piercing element has sufficient column strength to allow the userto press the sensor unit through the skin using the force from a thumbor finger, without substantial buckling of the tissue-piercing element.Accordingly, the structure of the tissue-piercing unit does not failwhen it is subjected to resistance (e.g., axial force) associated withthe penetration of tissue and skin. In some embodiments, thetissue-piercing element may have a column strength capable ofwithstanding an axial load greater than about 0.5 Newtons (N), orgreater than about 1 N, or greater than about 2 N, or greater than about5 N, or greater than about 10 N, without substantial buckling. Often, anincrease in the column thickness of an object will also increase itscolumn strength. In some embodiments, the base 120 of the distal tip mayhave an outside diameter of from about 0.05 mm to about 1 mm, or fromabout 0.1 mm to about 0.5 mm, or from about 0.15 mm to about 0.3 mm, toprovide the desired column strength for the tissue-piercing element.

Some of the tissue-piercing elements described herein are configured toprotect the membrane of the sensor body. As described elsewhere herein,the membrane may be relatively delicate, and thus may be damaged duringinsertion of the sensor unit into the host. Consequently, any damagesustained by the membrane may affect the sensor device's performance andits ability to function properly. For example, in some embodiments oneor more portions of the tissue-piercing element 108 may be formed with across-sectional area (along a plane transverse to the longitudinal axisof the tissue-piercing element 108) larger than that of the sensor body110. By having a cross-sectional area larger than that of the sensorbody 110, the tissue-piercing element 108 of the sensor device 100 isconfigured to pierce the host's skin 104 and to open and define apassage for insertion of the sensor body 110 into the tissue. Thus, therisk of a penetration-resistance force damaging and/or stripping themembrane 140 off from the rest of the sensor body 110 during theinsertion process is reduced. In some embodiments, the largest dimensionof the cross section transverse to a longitudinal axis of thetissue-piercing element 108 is less than about 0.1 mm, or less thanabout 0.05 mm, or less than about 0.03 mm.

In some embodiments, one or more layers of one or more polymers and/orbioactive agents may be coated onto the tissue-piercing element. The useof bioactive agents to coat the surface of the tissue-piercing elementmay provide a release of bioactive agents in the subcutaneous tissueduring and/or after insertion of the in vivo portion of the sensordevice. In further embodiments, one or more polymer layers may be usedto control the release rate of the one or more bioactive agents. Suchpolymers may include, but are not limited to, parylene, parylene C,parylene N, parylene F, poly(hydroxymethyl-p-xylylene-co-p-xylylene)(PHPX), poly(lactic-co-glycolic acid) (PLGA), polyethylene-co-vinylacetate (PEVA), Poly-L-lactic acid (PLA), poly N-butyl methacrylate(PBMA), phosphorylcholine, poly(isobutylene-co-styrene), polyoxyethylene(POE), polyglycolide (PGA), (poly(L-lactic acid), poly(amic acid) (PAA,polyethylene glycol (PEG), derivatives of one or more of these polymers,and combinations or mixtures thereof.

In some embodiments, one or more regions of the surface of thetissue-piercing element may comprise one or more recessed portions(e.g., cavities, indentations, openings, grooves, channels, etc.)configured to serve as reservoirs or depots for holding bioactiveagents. The recessed portions may be formed at any preselected locationand have any preselected depth, size, geometrical configuration, anddimensions, in accordance with the intended application. Use ofreservoirs or depots may increase the amount of bioactive agents thetissue-piercing element is capable of carrying and delivering. Infurther embodiments, the tissue-piercing element may be hollow with acavity and connected via various passages with one or more openings onits surface, so that bioactive agents may be released from the cavityvia the openings. In some embodiments, for example as shown FIGS. 3A and3B, the tissue-piercing element 310 comprises a pocket 312 shaped anddimensioned to support a sensor 314 with a membrane disposed thereon.

In certain embodiments, the in vivo portion of the sensor device isconfigured to remain substantially stationary within the tissue of thehost, so that migration or motion of the sensor body with respect to thesurrounding tissue is inhibited. Migration or motion may causeinflammation at the sensor implant site due to irritation, and may alsocause noise on the sensor signal due to motion-related artifacts.Therefore, it may be advantageous to provide an anchoring mechanism thatprovides support for the in vivo portion of the sensor device to avoidthe aforementioned problems. In some embodiments, the tissue-piercingelement may comprise a surface with one or more regions that aretextured. Texturing may roughen the surface of the tissue-piercingelement and thereby provide a surface contour with a greater surfacearea than that of a non-textured (e.g., smooth) surface. Accordingly,the amount of bioactive agents, polymers, and/or coatings that thetissue-piercing element may carry and be released in situ is increased,as compared to that with a non-textured surface. Furthermore, it isbelieved that a textured surface may also be advantageous in someinstances, because the increased surface area may enhance immobilizationof the in vivo portion of the sensor device within the tissue of thehost. In certain embodiments, the tissue-piercing element may comprise asurface topography with a porous surface (e.g. porous parylene), ridgedsurface, etc. In certain embodiments, the anchoring may be provided byprongs, spines, barbs, wings, hooks, a bulbous portion (for example, atthe distal end), an S-bend along the tissue-piercing element, agradually changing diameter, combinations thereof, etc., which may beused alone or in combination to stabilize the sensor within thesubcutaneous tissue. For example, in certain embodiments, thetissue-piercing element may comprise one or more anchoring membersconfigured to splay outwardly (e.g., in a direction toward a planeperpendicular to the longitudinal axis of the sensor unit) during orafter insertion of the sensor unit. Outward deployment of the anchoringmember facilitates anchoring of the sensor unit, as it results in thetissue-piercing element pressing against the surrounding tissue, andthus reduces (or prevents) movement and/or rotation of the sensor unit.In some embodiments, the anchoring members are formed of a shape memorymaterial, such as nitinol, which may be configured to transform from amartensitic state to an austenitic state at a specific temperature(e.g., room temperature or body temperature). In the martensitic state,the anchoring members are ductile and in a contracted configuration. Inthe austenitic state, the anchoring members deploy to form a largerpredetermined shape while becoming more rigid. While nitinol isdescribed herein as an example of a shape memory material that may bechosen to form the anchoring member, it should be understood that othersimilar materials (e.g., shape memory material) may also be used.

The tissue-piercing element of the sensor device may be introducedsubcutaneously at any of a variety of angles with respect to themounting surface (the bottom surface of the mounting unit), and thus theskin surface. For example, in some embodiments the distal tip of thetissue-piercing element may extend substantially perpendicular to themounting surface, but in other embodiments, the distal tip may extend atan angle with respect to the mounting surface of about 15°, 20°, 30°,40°, 45°, 60°, 75°, 80°, 90°, 105°, 100°, 120°, 135°, 140°, 150°, 160°,or 165°, for example.

In alternative embodiments, to provide protection of the membrane duringinsertion of the sensor device, the sensor body may be embedded orencapsulated in a needle formed of a biodegradable material. Followinginsertion, the needle gradually biodegrades, leaving behind the sensorbody which may then be activated. Any of a variety of biodegradablematerials (e.g., a non-interfering carbohydrate) may be used. In someembodiments, the biodegradable material may include a certainconcentration of an analyte to be measured, so that an initialcalibration point of the sensor device may be provided.

As illustrated in FIG. 1, the sensor device 100 may include askin-contacting mounting unit 116 configured to be secured to a host. Insome embodiments, the mounting unit 116 comprises a base 122 adapted forfastening to a host's skin. The base 122 may be formed from a variety ofhard or soft materials and may comprise a low profile for reducingprotrusion of the sensor device from the host during use. In someembodiments, the base 122 is formed at least partially from a flexiblematerial configured to conform to skin contour, so as to reduce oreliminate motion-related artifacts associated with movement by the host.In certain embodiments, the base 122 of the mounting unit 116 includesan adhesive material or adhesive layer 124, also referred to as anadhesive pad, preferably disposed on the mounting unit's bottom surface,and may include a releasable backing layer (not shown). Thus, removingthe backing layer and pressing the base 122 of the mounting unit 116onto the host's skin 104 adheres the mounting unit 116 to the host'sskin 104. Appropriate adhesive layers may be chosen and designed tostretch, elongate, conform to, and/or aerate the region (e.g. host'sskin). In some embodiments, the mounting unit comprises a guidingportion (not shown) configured to guide insertion of the sensor device100 through the host's skin 104 and to support a column strength of thesupport member 112 such that the sensor device 100 is capable of beinginserted through the host's skin 104 without substantial buckling.

While FIG. 1 illustrates one configuration for providing membraneprotection, other sensor body configurations may also be used. Forexample, some of the sensor bodies described herein may include asupport member 330 configured to partially surround a sensor, asillustrated in FIGS. 3A and 3B, or configured to substantially surrounda sensor, as illustrated in FIG. 3C. Unlike other embodiments describedelsewhere herein, in the embodiments illustrated in FIGS. 3A-3D, thesupport member 330 does not comprise a working electrode. Rather, one ormore working electrodes are arranged as components distinct from thesupport member 330. In some embodiments, the support member 330 may alsoserve as a reference electrode.

In the embodiment illustrated in FIG. 3A, the support member 330comprises a longitudinal recess 332 configured to at least partiallyaccommodate a sensor (e.g., a working electrode with a membrane disposedthereon). In some embodiments, the longitudinal recess may have a lengthcorresponding to less than about 90% of the length of the support member330, or less than about 75%, or less than about 50%, or less than about33%, or less than about 25%. In other embodiments, the longitudinalrecess may extend substantially across the entire length of the supportmember 330, as illustrated in FIG. 3B. In certain embodiments, thesupport member 330 may surround more than about 10% of the outerperimeter (e.g., circumference) of the sensor, or more than about 25%,or more than about 33%, or more than about 50%, or more than about 75%.

As illustrated in FIG. 3C, in some embodiments wherein the sensor (e.g.,the working electrode) is substantially surrounded by the support member330. The support member 330 may be provided with one or more windowportions 334 (openings or slots extending through the wall thickness ofthe support member 330) that expose certain portions of the electrode tobiological fluid (e.g., interstitial fluid), and thus allow biologicalfluid to diffuse toward and contact the working electrode'selectroactive surface and the membrane disposed thereon. In thisembodiment, the working electrode and the membrane disposed thereon areessentially housed within the support member 330, and are thus protectedduring packing, handling, and/or insertion of the device. The windowportions 334 may have any of a variety of shapes and dimensions. Forexample, in some embodiments, the window portions may be formed to havea circular or substantially circular shape, but in other embodiments,the electrode may be formed with a shape resembling an ellipse, apolygon (e.g., triangle, square, rectangle, parallelogram, trapezoid,pentagon, hexagon, octagon), or the like. In certain embodiments, thewindow portions may comprise sections that extend around the perimeterof the longitudinal cross section of the support member. For example,the support member may be made by using a hypo-tube with window portionscut out in a spiral configuration, by ablation, etching, or othertechniques.

Permeability

Conventional glucose sensors measure current in the nanoAmp range. Incontrast to conventional glucose sensors, the preferred embodiments areconfigured to measure the current flow in the picoAmp range, and in someembodiments, femtoAmps. Namely, for every unit (mg/dL) of glucosemeasured, at least one picoAmp of current is measured. In someembodiments, from about 1, 2, 3, 4, or 5 picoAmps to about 25, 50, 100,250, or 500 picoAmps of current is measured for every unit (mg/dl) ofglucose measured.

Bioactive Agents

A variety of bioactive agents are known to promote fluid influx orefflux. Accordingly, incorporation of bioactive agents into the membranemay increase fluid bulk, bulk fluid flow, and/or diffusion rates (andpromoting glucose and oxygen influx), thereby decrease non-constantnoise. In some embodiments, fluid bulk and/or bulk fluid flow areincreased at (e.g., adjacent to the sensor exterior surface) the sensorby incorporation of one or more bioactive agents. In some embodiments,the sensor is configured to include a bioactive agent that irritates thewound and stimulates the release of soluble mediators that are known tocause a local fluid influx at the wound site. In some embodiments, thesensor is configured to include a vasodilating bioactive agent, whichmay cause a local influx of fluid from the vasculature.

A variety of bioactive agents may be found useful in preferredembodiments. Example bioactive agents include but are not limited toblood-brain barrier disruptive agents and vasodilating agents,vasodilating agents, angiogenic factors, and the like. Useful bioactiveagents include but are not limited to mannitol, sodium thiosulfate,VEGF/VPF, NO, NO-donors, leptin, bradykinin, histamines, bloodcomponents, platelet rich plasma (PRP), matrix metalloproteinases (MMP),Basic Fibroblast Growth Factor (bFGF), (also known as Heparin BindingGrowth Factor-II and Fibroblast Growth Factor II), Acidic FibroblastGrowth Factor (aFGF), (also known as Heparin Binding Growth Factor-I andFibroblast Growth Factor-I), Vascular Endothelial Growth Factor (VEGF),Platelet Derived Endothelial Cell Growth Factor BB (PDEGF-BB),Angiopoietin-1, Transforming Growth Factor Beta (TGF-Beta), TransformingGrowth Factor Alpha (TGF-Alpha), Hepatocyte Growth Factor, TumorNecrosis Factor-Alpha (TNF-Alpha), Placental Growth Factor (PLGF),Angiogenin, Interleukin-8 (IL-8), Hypoxia Inducible Factor-I (HIF-1),Angiotensin-Converting Enzyme (ACE) Inhibitor Quinaprilat, Angiotropin,Thrombospondin, Peptide KGHK, Low Oxygen Tension, Lactic Acid, Insulin,Leptin, Copper Sulfate, Estradiol, prostaglandins, cox inhibitors,endothelial cell binding agents (for example, decorin or vimentin),glenipin, hydrogen peroxide, nicotine, and Growth Hormone. Still otheruseful bioactive agents include enzymes, cytotoxic or necrosing agents(e.g., pactataxyl, actinomycin, doxorubicin, daunorubicin, epirubicin,bleomycin, plicamycin, mitomycin), cyclophosphamide, chlorambucil,uramustine, melphalan, bryostatins, inflammatory bacterial cell wallcomponents, histamines, pro-inflammatory factors and the like.

Bioactive agents may be added during manufacture of the sensor byincorporating the desired bioactive agent in the manufacturing materialfor one or more sensor layers or into an exterior biomaterial, such as aporous silicone membrane. For example, bioactive agents may be mixedwith a solution during membrane formation, which is subsequently appliedonto the sensor during manufacture. Alternatively, the completed sensormay be dipped into or sprayed with a solution of a bioactive agent, forexample. The amount of bioactive agent may be controlled by varying itsconcentration, varying the indwell time during dipping, applyingmultiple layers until a desired thickness is reached, and the like, asdisclosed elsewhere herein. In an alternative embodiment, the bioactiveagent is microencapsulated before application to the sensor. Forexample, microencapsulated bioactive agent may be sprayed onto acompleted sensor or incorporated into a structure, such as an outer meshlayer or a shedding layer. Microencapsulation may offer increasedflexibility in controlling bioactive agent release rate, time of releaseoccurrence and/or release duration.

Chemical systems/methods of irritation may be incorporated into anexterior sensor structure, such as the biointerface membrane (describedelsewhere herein) or a shedding layer that releases the irritating agentinto the local environment. For example, in some embodiments, a“shedding layer” releases (e.g., sheds or leaches) molecules into thelocal vicinity of the sensor and may speed up osmotic fluid shifts. Insome embodiments, a shedding layer may provide a mild irritation andencourage a mild inflammatory/foreign body response, thereby preventingcells from stabilizing and building up an ordered, fibrous capsule andpromoting fluid pocket formation.

A shedding layer may be constructed of any convenient, biocompatiblematerial, include but not limited to hydrophilic, degradable materialssuch as polyvinylalcohol (PVA), PGC, Polyethylene oxide (PEO),polyethylene glycol-polyvinylpyrrolidone (PEG-PVP) blends, PEG-sucroseblends, hydrogels such as polyhydroxyethyl methacrylate (pHEMA),polymethyl methacrylate (PMMA) or other polymers with quickly degradingester linkages. In certain embodiment, absorbable suture materials,which degrade to compounds with acid residues, may be used. The acidresidues are chemical irritants that stimulate inflammation and woundhealing. In certain embodiments, these compounds include glycolic acidand lactic acid based polymers, polyglactin, polydioxone, polydyconate,poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly(caprolactone) homopolymers and copolymers, and the like.

In other example embodiments, the shedding layer may be a layer ofmaterials listed elsewhere herein for the first domain, includingcopolymers or blends with hydrophilic polymers such aspolyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,polyvinylalcohol, polyacrylic acid, polyethers, such as polyethyleneglycol, and block copolymers thereof including, for example, di-block,tri-block, alternating, random and graft copolymers (block copolymersare discussed in U.S. Pat. No. 4,803,243 and U.S. patent). In onepreferred embodiment, the shedding layer is comprised of polyurethaneand a hydrophilic polymer. For example, the hydrophilic polymer may bepolyvinylpyrrolidone. In one preferred embodiment, the shedding layer ispolyurethane comprising not less than 5 weight percentpolyvinylpyrrolidone and not more than 45 weight percentpolyvinylpyrrolidone. Preferably, the shedding layer comprises not lessthan 20 weight percent polyvinylpyrrolidone and not more than 35 weightpercent polyvinylpyrrolidone and, most preferably, polyurethanecomprising about 27 weight percent polyvinylpyrrolidone.

In other example embodiments, the shedding layer may include a siliconeelastomer, such as a silicone elastomer and a poly(ethylene oxide) andpoly(propylene oxide) co-polymer blend, as disclosed in copending U.S.patent application Ser. No. 11/404,417 filed on Apr. 14, 2006. In oneembodiment, the silicone elastomer is a dimethyl- andmethylhydrogen-siloxane copolymer. In one embodiment, the siliconeelastomer comprises vinyl substituents. In one embodiment, the siliconeelastomer is an elastomer produced by curing a MED-4840 mixture. In oneembodiment, the copolymer comprises hydroxy substituents. In oneembodiment, the co-polymer is a triblock poly(ethyleneoxide)-poly(propylene oxide)-poly(ethylene oxide) polymer. In oneembodiment, the co-polymer is a triblock poly(propyleneoxide)-poly(ethylene oxide)-poly(propylene oxide) polymer. In oneembodiment, the co-polymer is a PLURONIC® polymer. In one embodiment,the co-polymer is PLURONIC® F-127. In one embodiment, at least a portionof the co-polymer is cross-linked. In one embodiment, from about 5% w/wto about 30% w/w of the membrane is the co-polymer.

A shedding layer may take any shape or geometry, symmetrical orasymmetrical, to promote fluid influx in a desired location of thesensor, such as the sensor head or the electrochemically reactivesurfaces, for example. Shedding layers may be located on one side ofsensor or both sides. In another example, the shedding layer may beapplied to only a small portion of the sensor or the entire sensor.

In one example embodiment, a shedding layer comprising polyethyleneoxide (PEO) is applied to the exterior of the sensor, where the tissuesurrounding the sensor may directly access the shedding layer. PEOleaches out of the shedding layer and is ingested by local cells thatrelease pro-inflammatory factors. The pro-inflammatory factors diffusethrough the surrounding tissue and stimulate an inflammation responsethat includes an influx of fluid. Accordingly, early noise may bereduced or eliminated and sensor function may be improved.

In another example embodiment, the shedding layer is applied to thesensor in combination with an outer porous layer, such as a mesh or aporous biointerface as disclosed elsewhere herein. In one embodiment,local cells access the shedding layer through the through pores of aporous silicone biointerface. In one example, the shedding layermaterial is applied to the sensor prior to application of the poroussilicone. In another example, the shedding layer material may beabsorbed into the lower portion of the porous silicone (e.g., theportion of the porous silicone that will be proximal to the sensor afterthe porous silicone has been applied to the sensor) prior to applicationof the porous silicone to the sensor.

Wound Suppression

Non-constant noise may be decreased by wound suppression (e.g., duringsensor insertion), in some embodiments. Wound suppression includes anysystems or methods by which an amount of wounding that occurs uponsensor insertion is reduced and/or eliminated. While not wishing to bebound by theory, it is believed that if wounding is suppressed or atleast significantly reduced, the sensor will be surrounded bysubstantially normal tissue (e.g., tissue that is substantially similarto the tissue prior to sensor insertion). Substantially normal tissue isbelieved to have a lower metabolism than wounded tissue, producing fewerinterferents and reducing early noise.

Wounds may be suppressed by adaptation of the sensor's architecture toone that either suppresses wounding or promotes rapid healing, such asan architecture that does not cause substantial wounding (e.g., anarchitecture configured to prevent wounding), an architecture thatpromotes wound healing, an anti-inflammatory architecture, etc. In oneexample embodiment, the sensor is configured to have a low profile, azero-footprint or a smooth surface. For example, the sensor may beformed of substantially thin wires, such as wires from about 50 μm toabout 116 μm in diameter, for example. Preferably, the sensor is smallenough to fit within a very small gauge needle, such as a 30, 31, 32,33, 34, or 35 gauge needle (or smaller) on the Stubs scale, for example.In general, a smaller needle, the more reduces the amount of woundingduring insertion. For example, a very small needle may reduce the amountof tissue disruption and thereby reduce the subsequent wound healingresponse. In an alternative embodiment, the sensor's surface is smoothedwith a lubricious coating, to reduce wounding upon sensor insertion.

Wounding may also be reduced by inclusion of wound-suppressive agents(bioactive agents) that either reduce the amount of initial wounding orsuppress the wound healing process. While not wishing to be bound bytheory, it is believed that application of a wound-suppressing agent,such as an anti-inflammatory, an immunosuppressive agent, ananti-infective agent, or a scavenging agent, to the sensor may create alocally quiescent environment and suppress wound healing. In a quiescentenvironment, bodily processes, such as the increased cellular metabolismassociated with wound healing, may minimally affect the sensor. If thetissue surrounding the sensor is undisturbed, it may continue its normalmetabolism and promote sensor function.

In some embodiment, useful compounds and/or factors for suppressingwounding include but are not limited to first-generation H₁-receptorantagonists: ethylenediamines (e.g., mepyramine (pyrilamine),antazoline), ethanolamines (e.g., diphenhydramine, carbinoxamine,doxylamine, clemastine, and dimenhydrinate), alkylamines (pheniramine,chlorphenamine (chlorpheniramine), dexchlorphenamine, brompheniramine,and triprolidine), piperazines (cyclizine, hydroxyzine, and meclizine),and tricyclics (promethazine, alimemazine (trimeprazine),cyproheptadine, and azatadine); second-generation H₁-receptorantagonists such as acrivastine, astemizole, cetirizine, loratadine,mizolastine, azelastine, levocabastine, and olopatadine; mast cellstabilizers such as cromoglicate (cromolyn) and nedocromil;anti-inflammatory agents, such as acetometaphen, aminosalicylic acid,aspirin, celecoxib, choline magnesium trisalicylate, diclofenacpotassium, diclofenac sodium, diflunisal, etodolac, fenoprofen,flurbiprofen, ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein,anti-IL-6 iNOS inhibitors (e.g., L-NMDA), Interferon, ketoprofen,ketorolac, leflunomide, melenamic acid, mycophenolic acid, mizoribine,nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib,salsalate, sulindac, and tolmetin; corticosteroids such as cortisone,hydrocortisone, methylprednisolone, prednisone, prednisolone,betamethesone, beclomethasone dipropionate, budesonide, dexamethasonesodium phosphate, flunisolide, fluticasone propionate, paclitaxel,tacrolimus, tranilast, triamcinolone acetonide, betamethasone,fluocinolone, fluocinonide, betamethasone dipropionate, betamethasonevalerate, desonide, desoximetasone, fluocinolone, triamcinolone,triamcinolone acetonide, clobetasol propionate, and dexamethasone;immunosuppressive and/or immunomodulatory agents such asanti-proliferative, cell-cycle inhibitors (e.g., paclitaxel,cytochalasin D, infiximab), taxol, actinomycin, mitomycin, thospromoteVEGF, estradiols, NO donors, QP-2, tacrolimus, tranilast, actinomycin,everolimus, methothrexate, mycophenolic acid, angiopeptin, vincristing,mitomycine, statins, C MYC antisense, sirolimus (and analogs),RestenASE, 2-chloro-deoxyadenosine, PCNA Ribozyme, batimstat, prolylhydroxylase inhibitors, PPARγ ligands (for example troglitazone,rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors,probucol, BCP671, EPC antibodies, catchins, glycating agents, endothelininhibitors (for example, Ambrisentan, Tesosentan, Bosentan), Statins(for example, Cerivastatin), E. coli heat-labile enterotoxin, andadvanced coatings; anti-infective agents, such as anthelmintics(mebendazole); antibiotics such as aminoclycosides (gentamicin,neomycin, tobramycin), antifungal antibiotics (amphotericin b,fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin,micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime,ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactamantibiotics (cefotetan, meropenem), chloramphenicol, macrolides(azithromycin, clarithromycin, erythromycin), penicillins (penicillin Gsodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin,piperacillin, ticarcillin), tetracyclines (doxycycline, minocycline,tetracycline), bacitracin; clindamycin; colistimethate sodium; polymyxinb sulfate; vancomycin; antivirals including acyclovir, amantadine,didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine,nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir,valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin);sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone);furazolidone; metronidazole; pentamidine; sulfanilamidum crystallinum;gatifloxacin; and sulfamethoxazole/trimethoprim; interferent scavengers,such as superoxide dismutase (SOD), thioredoxin, glutathione peroxidaseand catalase, anti-oxidants, such as uric acid and vitamin C, ironcompounds, Heme compounds, and some heavy metals; artificial protectivecoating components, such as albumin, fibrin, collagen, endothelialcells, wound closure chemicals, blood products, platelet-rich plasma,growth factors and the like.

While not wishing to be bound by theory, it is believed that, inaddition to the analyte sensor configurations described elsewhereherein, application of a lubricious coating to the sensor maysubstantially reduce and/or suppress noise occurrence by substantiallypreventing injury to the host. Accordingly, in some embodiments, alubricious coating may be applied to the in vivo portion of the sensorto reduce the foreign body response to the implanted sensor. The term“lubricous coating” as used herein is used in its ordinary sense,including without limitation, a surface treatment that provides areduced surface friction. A variety of polymers are suitable for use asa lubricious sensor coating, such as but not limited to Teflon,polyethylene, polycarbonate, polyurethane, poly(ethylene oxide),poly(ethylene oxide)-poly(propylene oxide) copolymers, and the like. Inone example embodiment, one or more layers of HydroMed™, apolyether-polyurethane manufactured by CardioTech International, Inc.(Wilmington, Mass.) is applied to the sensor (e.g., over the resistancedomain).

Dissolvable Tip

Sensors such as those described above are sometimes referred to as“tack” sensors, due to their resemblance to a thumbtack. One aspect ofthe present embodiments includes the realization that tack sensorsinclude a sharpened tip that remains implanted in the tissue throughoutthe usable life of the sensor. Leaving the sharpened tip in vivo for anextended period of time may cause trauma to surrounding tissue, leadingto scarring and inhibition of wound healing. Some of the presentembodiments provide solutions to this problem. In some embodiments, thetip is configured to dissolve during the implantable sensor session, forexample, within about 3, 5, 7 or 10 days.

As described above, and with reference to FIG. 1, the tissue-piercingelement 108 may be a discrete component, separate from, for example, thesensor body 112. In such embodiments, the sensor body 112 may include ablunt tip or distal face 126. The tissue-piercing element 108 similarlyincludes a blunt proximal face 128 that abuts the sensor body tip 126.As described above, the tissue-piercing element 108 may or may not besecured to the sensor body 112.

In some embodiments, the tissue-piercing element 108 may comprise abiodegradable material, or a material that rapidly dissolves uponinsertion into the host. Upon implantation, degradation of thetissue-piercing element 108 may be spontaneous with acid residues. Insuch embodiments, any sensor membrane(s) is desirably pH insensitive. Arate of degradation of the tissue-piercing element 108 depends upon theamount of tip material present. For example, the material maybiodegrade/dissolve within three days after insertion into the host, orwithin two days, or one day, or twelve hours, or six hours, or threehours, or two hours, or one hour. In certain embodiments, the materialmay dissolve within a timeframe before which the sensor beginsoperating. In such embodiments, the dissolved material of thetissue-piercing element 108 may not interfere with sensor calibration.

Example materials for the tissue-piercing element 108 include at leastone of a salt, a metallic salt, a sugar, a synthetic polymer, a glue oradhesive (such as cyanoacrylate), polylactic acid (PLA), polyglycolicacid, poly(lactic-co-glycolic acid) (PLGA), a polyanhydride, apolyphosphazene, or any material with glass-like properties. Inparticular, PLA, PLGA, and polyanhydrides all have sufficient hardnessfor this type of application. For example, a hardness of thetissue-piercing element 108 may be in the range of 35 D to 55 D, such asfor example 45 D.

In some embodiments, the material of the tissue-piercing element 108 maybe tuned or modified to achieve desired properties, such as dissolutiontime, hardness, etc. For example, the tissue-piercing element 108 may beprocessed with annealing and hardening cycles, and/or cross-linking.Cross-linking may be, for example, light based, such as irradiation withUV light. In some embodiments, the tuning may comprise combiningmaterials. For example, the hardness of the tissue-piercing element 108may be improved by incorporating hydroxyapatite in a blend, similar tosome bone implants. Such a blend dramatically increases hardness. Also,these inclusions tend to lead to faster dissolution times.

If a polymer material is selected for the tissue-piercing element 108,it may have a crystallinity, which can also be defined by a RockwellHardness. For example, the material may have a Rockwell Hardness ofabout 25D-65D, such as about 45D. An adequate Rockwell Hardness enablesthe polymer to undergo various processing steps without tearing ordamage to the polymer.

In some embodiments, the tissue-piercing element 108 may comprise acoating that covers at least a portion of the sensor body 112, includingthe sensor tip 126. For example, with reference to FIG. 4, a length L ofthe distal end of the sensor body 412 and membrane 414 may be dipped ina liquid bath (not shown). The length L may be chosen to coat enough ofthe sensor tip to achieve good adhesion without covering any electrodeson the sensor. For example, L may in the range of 0.1-4 mm, such as 2-3mm. As the sensor is withdrawn from the bath, the coating remains overthe length L, and extends distally from the sensor body tip 426, forminga dissolvable tissue-piercing tip 408. After the coating cures, theportion extending from the sensor tip may be sharpened to produce atissue-piercing coating tip 418.

In certain example embodiments, a viscosity of the liquid bath is below100 cP, and the withdrawal rate is 20-30 in/sec, with an immediateexposure to UV (or heat) cross-linking to cure and build thickness. Atip mold or draw-through fixture that clamps and cures in one step inorder to form a sharp cone shape is advantageous.

Another embodiment to create a sharp sensor tip with a polymer is toapply a voltage to the material while it is being cured. The voltagecauses the polymer to modify its shape to a point. The sharp tip remainswhen the curing is completed and the voltage is removed. Curing couldcomprise irradiating, drying, heating, etc. Another embodiment comprisesheating the material and drawing it out like glass.

As discussed above, the sensor 400 may include one or more aspects thateither suppress wounding, or promote rapid healing, or both. In certainembodiments, these aspects may be present in the dissolvable tip 408.For example, one or more bioactive agents may be integrated into thedissolvable tip 408 by combining it with the material of the liquid bathduring the dipping process. Alternatively, before or after curing, thedissolvable tip 408 may be dipped in a subsequent liquid bath that coatsthe dissolvable tip 408 with one or more bioactive agents. Examplebioactive agents are discussed at length above and will not be repeatedhere. However, certain bioactive agents may, for example, induce osmoticpressure or oncotic pressure.

In certain embodiments, the material of the dissolvable tip 408 may havean effect on the sensor 400. For example, if the dissolvable tip 408 isa salt, it could set up an osmotic pressure gradient that may pullfluids to the tissue surrounding the sensor 400, causing it to startupfaster or avoid early signal attenuation.

Dissolvable Needle

Some of the present embodiments relate to sensors that require a needlefor insertion into the host. For example, with reference to FIG. 5, thesensor 500 may be contained within a lumen 504 of a needle 502. Anotheraspect of the present embodiments includes the realization that the needto remove the needle after sensor insertion adds complexity to theinsertion process, including the need to electrically connect the sensorto sensor electronics after insertion. Some of the present embodimentsprovide solutions to this problem.

With reference to FIG. 5, the needle 502 may be similar to a standardhypodermic needle 502, including a lumen 504 and a sharp distal tip 506.However, the material of the needle 502 may be biodegradable, or capableof dissolving after insertion into a host. The material and materialproperties of the needle 502 may be similar to those discussed abovewith respect to the dissolvable tissue-piercing tip 506. These materialsand material properties are discussed at length above, and will not berepeated here. However, polyanhydrides are one particularly advantageousmaterial for the needle 502, as they may form tubes readily and those inturn may be sharpened by cutting.

In some embodiments, the sensor 500 may be received within the lumen 504but not attached to the needle 502 (FIG. 5), for example may be held viafriction force within the needle and/or couple to a base, such as base122 as shown in FIG. 1. In other embodiments, the sensor 500 may beattached to the needle 502 (FIG. 6) using mechanical or chemicalcoupling methodologies, as may be appreciated by one skilled in the art.

In the present embodiments, since the needle 502 isbiodegradable/dissolvable, it does not need to be removed from the hostafter the sensor 500 is inserted. Instead, the needle 502 harmlesslybiodegrades, thereby eliminating the traumatic tip 506 and leavingbehind the sensor 500. The dissolvable needle 502 thus simplifies theprocess of inserting the sensor 500 into the host. In addition, sincethe needle 502 does not need to be withdrawn, the sensor 500 may beelectrically connected to sensor electronics (not shown) prior toinsertion. This aspect advantageously eliminates the need to connect thesensor 500 to sensor electronics after insertion, which may bechallenging.

As with the embodiments of the dissolvable tissue-piercing tip 506discussed above, the present dissolvable needle 502 may include one ormore bioactive agents to suppress wounding and/or promote rapid woundhealing. These bioactive agents may be similar to those discussed above,and may be applied to/integrated into the needle 502 using the sametechniques discussed above.

In certain embodiments, the needle 502 may be at least partiallydissolvable. In such embodiments, the needle may have stronger andweaker (or more and less dissolvable) portions, such that in vivo theweaker portions dissolve more quickly and the stronger portions thenbreak away from one another. The stronger portions may ultimatelydissolve, albeit more slowly than the weaker portions. Such embodimentsmay be described as “fractionate,” referring to how the weaker portionsdissolve quickly allowing the hard segments, such as PLA or PGA, thatprovide sufficient strength during insertion, to fragment away, whilenot harming the body during or after sensor insertion.

Membrane Hardening Agent

One aspect of the present embodiments includes the realization that thematerial of analyte sensor membranes is soft, and tends to peel back asthe sensor advances into tissue. This problem is especially acute forsensors that are formed by a process in which they are first coated witha membrane and then sharpened at the tip. This process exposes thesensor body, and leaves a thin coating of the membrane surrounding thesides of the sensor body at the tip. Some of the present embodimentsprovide solutions to this problem.

FIG. 7 illustrates a sensor unit 700 similar to the sensor device 100described above and shown in FIG. 1. The sensor unit 700 includes asensor body 702 at least partially covered by a membrane 704. Ratherthan having a discrete tissue-piercing element, as in the previousembodiments, instead the distal end 706 of the sensor body 702 andmembrane 704 are sharpened to form a tissue-piercing tip 708. Since thesensor is sharpened after being coated with the membrane 704, a portionof the sensor body 702 is exposed at the sharpened tip 708. In analternative embodiment illustrated in FIG. 8, the sensor body 802 may besharpened prior to being coated with the membrane 804, so that thesharpened tip 808 is covered with membrane 804.

In the embodiments of FIGS. 7 and 8, the distal end of the sensor body702/802 may be sharpened by any of a variety of methods, such as laserablation, mechanical grinding, diamond wire, high-speed milling,abrasive water jet cutting, electric discharge machining by wire orplunge, electrochemical machining, electrochemical etching,electrochemical polishing, stamping, or any other method.

In both of the embodiments illustrated in FIGS. 7 and 8, the softmembrane 704, 804 is susceptible to peeling back as the sensor advancesthrough tissue during the process of being inserted into the host. Also,due to its very small diameter, the sensor of FIGS. 7 and 8 may lack thecolumn strength necessary to be inserted through the host's skin withoutsubstantial buckling. To solve these problems, certain of the presentembodiments provide a hardening agent 900 that either covers themembrane 902 (FIG. 9) or is integrated into the membrane 902 (FIG. 10).The hardening agent 900 provides increased column strength to the sensorbody 904 so that the sensor unit 906 is capable of being insertedthrough the host's skin 908 without substantial buckling. The hardeningagent 900 may also increase adhesion of the membrane 902 to the sensorbody 904 and/or stiffen the membrane 902 so that it is more resistant topeeling back as the sensor advances through tissue during the process ofbeing inserted into the host. Preferably, however, the hardening agent900 allows analyte permeability within the membrane 902 so that theability of the sensor to function is not compromised.

While FIGS. 9 and 10 illustrate embodiments in which a tip 910 of thesensor body 904 is exposed through the membrane 902/hardening agent 900,the present embodiments also contemplate that the tip 910 of the sensorbody 904 could be covered by the membrane 902/hardening agent 900,similar to the embodiment of FIG. 8. Where the tip 910 of the sensorbody 904 is exposed through the membrane 902/hardening agent 900, incertain embodiments the material of sensor body 904 is selected so thatit does not react with a selected analyte and/or product of an analytereaction. Such a reaction may create background current, which mayadversely affect the performance of the sensor.

In one embodiment, the material of the sensor body 904 may be formedwith a core that does not react with hydrogen peroxide. One such sensorbody is platinum cladding on tantalum, where the tantalum core does notreact with hydrogen peroxide or create additional background signal dueto its electrochemical properties. The small amount of exposed platinummay not significantly contribute to the background signal.

In certain embodiments, the hardening agent 900 comprises cyanoacrylate.Cyanoacrylate is an advantageous material to use for this application,because it may permeate into the membrane, it cures quickly, it is veryhard, and it may be machined after curing if needed. Cyanoacrylate mayalso deaden any enzyme that is on the tip, and coat anyelectrochemically active surfaces. Other example materials includeepoxies and UV adhesives.

In one embodiment, a method of making a sensor device comprises coatinga wire with a membrane. The coated wire is then cut to a desired lengthto form a sensor wire having a tip. Example methods for performing thesesteps are described in U.S. Patent Publication No. 2011-0027453-A1, theentire contents of which are hereby incorporated by reference herein.The coated sensor wire is then exposed to a hardening agent such thatthe membrane absorbs the hardening agent. Then, if necessary, thehardening agent is cured.

Exposing the coated sensor wire to the hardening agent may comprisedipping at least the sensor tip in a liquid bath of the hardening agent.After the sensor wire is withdrawn from the liquid bath, the membrane iscured to harden the hardening agent. Thereafter, the sensor tip may besharpened to form a sharp point capable of piercing tissue. Inalternative embodiments, the sensor wire may be sharpened prior toapplying the membrane to the sensor wire, or after applying the membraneto the sensor wire but prior to applying the hardening agent.

In embodiments in which the sensor tip is sharpened after the membraneand hardening agent are applied, a deadening agent may be applied to thesharpened sensor tip to deaden any active surfaces exposed during thesharpening step. For example, platinum (Pt) or enzyme layer may beconsidered “active surfaces.” In some embodiments, the deadening agentmay comprise cyanoacrylate or a silane. Silanes may be particularlyadvantageous, since they may be lubricious, which may help the sensorpenetrate into skin.

In embodiments that include a deadening agent, the deadening agent maybe applied using vapor deposition, such as chemical vapor deposition(CVD) or physical vapor deposition (PVD). For example, a two-stepapplication process may be used comprising a masking agent and then aspray agent followed by a rinse cycle.

In another embodiment, a method of making a sensor device comprisescoating a wire with a membrane. The coated wire is then cut to a desiredlength to form a sensor wire having a tip. The coated wire is thenexposed to a hardening agent such that the hardening agent covers themembrane. Additional process steps may then proceed similar to those inthe foregoing embodiment, such as curing, sharpening, etc.

In another embodiment, a method of making a sensor device comprisescutting a wire to a desired length to form a sensor wire having a tip.The sensor tip is then sharpened to form a sharp point capable ofpiercing tissue. The sensor wire is then coated, including the sharpenedsensor tip, with a membrane. The coated sensor wire is then exposed to ahardening agent such that the membrane absorbs the hardening agent.Additional process steps may then proceed similar to those in theforegoing embodiment, such as curing, etc.

In another embodiment, a method of making a sensor device comprisescutting a wire to a desired length to form a sensor wire having a tip.The sensor tip is then sharpened to form a sharp point capable ofpiercing tissue. The sensor wire is then coated, including the sharpenedsensor tip, with a membrane. By coating the membrane, the host's fluidis separated from the enzyme by the protective membrane system, avoidingleaching of the enzyme into the host and ensuring a controlled pathwayof diffusion of the host's fluid through the membrane system, includingthe enzyme. The coated sensor wire is then exposed to a hardening agentsuch that the hardening agent covers the membrane. Additional processsteps may then proceed similar to those in the foregoing embodiment,such as curing, etc.

Stimulus Responsive Materials

In any of the embodiments described herein, the sensor body (e.g., wire)may be one or more “stimulus-responsive materials,” which are materialsthat change at least one property responsive to a stimulus. For example,the sensor body may be a shape memory metal (or a more rigid metal likeTi) and/or a shape memory polymer. In such embodiments, the sensor body,while in a first state, may be held in a first configuration, which maybe curved or straight. During or after the insertion process the wiretransitions to a second state, which may be curved or straight.

In some embodiments, the sensor is in a straight, rigid state at a firsttemperature, and in a curved, flexible state at a second temperature.During use, the sensor body's original temperature is transformed to thefirst temperature (e.g., by heating or cooling), thereby causing thesensor to become straight and rigid, i.e., properties that are conducivefor piercing of skin and tissue. After at least a portion of the senorpierces the skin and tissue, the sensor body reverts to a secondtemperature, at which it becomes curved and flexible, thereby providingcomfort for the patient wearing the sensor.

In yet another embodiment, the sensor body comprises one or more“stimulus-responsive materials” that provide tissue compliant mechanicalproperties upon insertion and application of stimulus. It isadvantageous to have the inserted body of the sensor conform to thenatural tissue construct and modulus to reduce the injury and foreignbody response caused by the presence of the sensor and body movement, assuch injury or foreign body response may adversely alter the output ofthe sensor. For example, the tensile modulus of the sensor body may bebetween about 0.5-10 kPa.

Examples of material properties that may be changed responsive to astimulus include, but are not limited to: hardness (e.g. from a hardnessequivalent to that of a typical needle ex vivo, to softness closer innature to subcutaneous tissue than a typical needle in vivo), shape,permeability, relative hydrophilicity, conformation of polymerorientation, etc. Examples of stimuli that may be used to changeproperties include, but are not limited to: temperature (e.g. 37° C. forin vivo change), pressure, hydration upon insertion to a subcutaneousenvironment, radiation (e.g. UV) provided by skin patch, electromagneticstimulus, such as via a voltage, magnetic field, such as via inductivefield, etc. Examples of stimulus-responsive materials include, but arenot limited to: polymers, such as shape memory polymers, polyurethane,polyester, polyamide, polyacrylate, polyether, and copolymers thereof,alloys such as shape memory alloys (e.g., copper-aluminum-nickel(Cu—Al—Ni), nickel-titanium (NiTi), iron-manganese-silicon (Fe—Mn—Si),or copper-zinc-aluminum (Cu—Zn—Al)), etc.

One example includes a sensor body formed from polyurethane that changesits elastic modulus by 10 x at 37° C. Other examples include a sensorbody formed from a polyurethane copolymer that softens upon electricalstimulus or radiation (e.g., UV) stimulus applied right after sensorinsertion, and others.

Sensors

Certain embodiments described herein provide various mechanisms fordirectly inserting a transcutaneous sensor into a host without the useof a separate applicator, i.e., other than the sensor device itself.Direct press insertion of a transcutaneous sensor (e.g., an electrode)having a wire-like geometry, especially a fine wire, may be technicallychallenging because of buckling risks associated with the sensor. Directpress insertion of a sensor also presents challenges relating to damageduring the insertion process to the membrane disposed on the sensor.Without membrane protection, the membrane may be stripped off the sensoror be mechanically damaged during the insertion process. It is alsodesirable to avoid having exposed metal (or other electricallyconductive material) at the tip of the sensor, because exposed metal maybe electroactive and add background signal (noise) and/or cause thesensitivity of the sensor to vary. The embodiments described herein aredesigned to overcome the aforementioned challenges by providingminiaturized sensor devices capable of providing structural support(e.g., in the form of mechanical/structural properties such as columnstrength) for direct insertion of a transcutaneous sensor, and capableof protecting the membrane from damage during the insertion process.

In some embodiments, the sensor is designed with a configuration thatenables printing of the electrodes (e.g., the working and/or referenceelectrode) onto the sensor body (e.g., the core). Unlike printingmaterials onto a planar substrate, printing materials (e.g., electrodematerials) onto a wire presents unique challenges, particularly withwires intended for implantation with a diameter less than 400 microns(μm), such as the case with many of the sensor embodiments describedherein. FIGS. 11-14 illustrate various sensor designs that enableprinting of electrodes onto a sensor body formed with a wire shape.

FIG. 11 is a front view of a sensor 1000, and FIG. 12 is a rear view ofthe sensor 1000. With reference to FIG. 11, the sensor 1000 comprises aconductive core wire 1002 with a nonconductive outer layer or jacket1004. The core wire 1002 in some embodiments may be a conductive metal,such as and without limitation platinum, tantalum, platinum-iridium, orin other embodiments may be formed of a nonconductive material (e.g., apolymer or a non-conductive metal). In some embodiments, a portion ofthe core wire 1002 may form an electrode (e.g., a working, reference, orcounter electrode). The nonconductive jacket 104 may be a polymer, suchas and without limitation polyurethane, parylene, silicone,polyurethane, polyimide, or polyamide-imide. Axially spaced electrodes1008, 1010 are provided over the nonconductive jacket 1004. In oneembodiment, the sensor comprises a first electrode formed from the corewire 1002, a second electrode 1008, and a third electrode 1010. Theelectrodes 1008, 1010 may be, for example and without limitation,platinum, platinum-iridium, carbon, silver, silver/silver chloride,and/or any other material known to be used to form an electrodes (e.g.,working, reference, or counter electrodes).

With reference to FIG. 12, the electrode 1008 does not extend around theentire circumference of the jacket 1004. The gap in the circumferencepermits a conductive trace 1012 to extend along the jacket 1004 betweenthe electrode 1010 and a conductive component 1006 configured to joinwith a contact (not shown). A layer of electrically insulative material1014 overlies the conductive trace 1012 to prevent contact between theconductive trace 1012 and the electrode 1008. In one example, the systemcomprises three electrodes, with the electrode 1008 comprising areference electrode or counter electrode and the first and thirdelectrodes 1002, 1010 comprising working electrodes. In anotherembodiment of a three-electrode system, the electrode 1010 serves as thereference or counter electrode, while the electrode 1008 serves as aworking electrode. In another example, the system comprises twoelectrodes. In one such embodiment, the core wire 1002 does not serve asa working electrode, and thus may be formed of a non-conductivematerial. In this embodiment, one of the electrodes 1008 or 1010 servesas the working electrode, while the other electrode 1008 or 1010 servesas the reference or counter electrode.

As previously noted, the sensor 1000 of FIGS. 11 and 12 mayadvantageously be formed by printing, such as by 3-D printing. Forexample, the second and third electrodes 1008, 1010 may be printed onthe exterior of the nonconductive jacket 1004. A distal end 1016 of thesensor 1000 may be sharpened to form a tissue piercing tip (not shown).

In embodiments in which the core 1002 does not serve as an electrode(e.g., in a two-electrode sensor system), the distal end 1016 of thecore 1002 of the sensor 1000 may be made non-electroactive, so that itdoes not produce background signal. For example, the conductive corewire 1002 at the distal end 1016 can be inactivated throughelectrochemical polymerization. In other embodiments, the distal end1016 of the senor may be capped by a non-conductive material, such as,for example, polyurethane, parylene, silicone, polyurethane, polyimide,polyamide-imide, or any other insulator(s).

FIGS. 13 and 14 illustrate another sensor 1020 configured for directpress insertion according to the present embodiments. FIG. 13 is a frontview of the sensor 1020, and FIG. 14 is a rear view of the sensor 1020.The sensor 1020 is somewhat similar to the sensor 1000 of FIGS. 11 and12, except that the core wire 1002 may be omitted. Instead, theelectrodes 1022, 1024, 1026 are provided over the nonconductive layer1028 and electrically connected to sensor electronics (not shown) withconductive traces 1030, 1032, 1034 provided on the outer surface of thenonconductive layer 1028, as shown in FIG. 14. In the embodiment shown,the electrode 1024 does not extend around the entire circumference ofthe nonconductive layer 1028, thereby providing a conductive path forelectrode 1026 around electrode 1024, without short circuit. Similarly,electrode 1022 also does not extend around the entire circumference ofthe nonconductive layer 1028, thereby providing conductive paths forelectrodes 1026 and 1028 around electrode 1022. Electrodes 1022, 1024,1026 may be a working electrode, a reference electrode, and/or a counterelectrode. For example, in one embodiment, electrode 1026 serves as aworking electrode, while electrode 1024 serves as a reference electrode,and electrode 1022 serves as a counter electrode. The elementsillustrated in FIGS. 11-14, as well as every other figure providedherein, may not be drawn to scale and are provided merely to illustrateand help better understand the present embodiments.

Although the embodiments shown in FIGS. 11-14 are designed to have aconfiguration that enables printing of the electrodes, such sensordesigns may, instead or in addition, be manufactured by any of a varietyof techniques described herein or elsewhere.

Often, the sensor geometry and membrane properties may be difficult tocontrol at the sharpened tip. There is also a potential for damage inthis area. Accordingly, it would be desirable for the tip not to be apart of the working electrode. Furthermore, because electrode material(e.g., platinum) is often expensive, reducing the use of suchmaterial(s) (e.g., by not having the tip be part of the electrode) maybe advantageous. FIG. 15 illustrates another sensor 1040 configured fordirect press insertion according to the present embodiments. In thisembodiment, the sensor 1040 includes a core wire 1042 and two electrodes1044, 1048 provided along the wire 1042. In alternative embodiments, thesensor may comprise one, three, four, five, or more electrodes, with atleast one of the electrodes being a working electrode, and at least oneof the electrodes being a counter or reference electrode. The core wire1042 may be formed of a conductive metal (e.g., tantalum or stainlesssteel) or a nonconductive material, such as a polymer or a nonconductivemetal.

Referring again to FIG. 15, the electrodes 1044, 1048 may comprise aconductive material, such as, but not limited to, platinum,platinum-iridium, carbon, silver, silver/silver chloride, and/or anyother material known to form an electrode (e.g., working, reference, orcounter electrodes). In one embodiment, both electrodes 1044, 1048 areworking electrodes and thus collectively form an array of workingelectrodes. In this particular embodiment, electrodes 1044, 1048 canshare a conductive trace or pathway. In another embodiment, oneelectrode is a working electrode, and the other electrode is a referenceor counter electrode. In some embodiments, the core wire 1042 may besurrounded by multiple layers of conductive materials with at least oneinsulating layer disposed between every two layers of conductivematerial. In these embodiments, the working electrodes each have theirown electrical connection to an electrical contact through theirindividual conductive layers.

In one process for making the sensor 1040, the core wire 1042 may bepositioned on a substrate 1046, and the electrodes 1044, 1048 may beprinted (e.g., by pad printing) onto the core wire 1042 with a platinumpaste. Any of a variety of printing techniques may be used, such as, butnot limited to pad printing or 3-D printing. Depositing a layer ofplatinum paste selectively along the length of a non-conductive corewire 1042 may advantageously reduce material use and maintain anon-electroactive sensor tip. In some embodiments, in which the wirecore 1042 is covered by multiple layers of conductive materials (withinsulting layers disposed therebetween), these conductive materials maybe formed of a conductive material that is not electroactive, such astantalum, for example. A layer of platinum or silver/silver chloride,both of which are both conductive and electroactive, can then be padprinted onto these conductive layers to form an electroactive surfaceand thereby to form an electrode. By using this method, the sensor canbe produced at lower cost, because the raw material costs for tantalumand other conductive, non-electroactive materials can be less than formaterials that are both conductive and electroactive (e.g., platinum).

Often there is a tradeoff between ease of sensor insertion and patientcomfort. A sensor formed of a rigid, inflexible material, all else beingequal, is less likely to buckle during sensor insertion than a sensorthat is soft and flexible. However, once implanted, because of itsrigidity and the inflexibility, such a sensor may not be comfortable tothe patient wearing the sensor, particularly if there is regularmovement at the sensor site. Conversely, a sensor formed of a soft,flexible material is more likely to buckle during sensor insertion, andthus may not be a viable sensor design for a direct insertionimplementation.

FIGS. 16 and 17 illustrate one concept that overcomes the twoabove-described design criteria. With reference to FIG. 16, the sensor1060 is formed on a flat substrate such as known planar substrate basedsensors. The sensor 1060 may incorporate any of the sensor features(e.g., an electroactive surface and a membrane) described herein and anyfeature found in any conventional implantable sensor. Prior to sensorinsertion, the flat sheet is rolled into a cylinder, as shown in FIG.17. The rolled cylindrical form imparts a column strength sufficient forpress insertion through the skin and tissue of the host during theimplantation procedure. Rolling the planar sensor creates an overlapregion 1062 where two opposite edges 1064, 1066 converge. Theoverlapping portions may be secured to one another, such as with anadhesive, a tie layer, a temporary bond, or the like, formed as would beappreciated by one skilled in the art. For example, an adhesive may beapplied in the overlap region 1062, wherein the adhesive dissolves afterthe sensor 1060 is implanted. Upon dissolution of the adhesive, therolled substrate may unroll to reassume its planar shape (FIG. 16). Theplanar sensor 1060 may be more pliable than the rolled sensor 1060,which may make the sensor 1060 more comfortable for the host.Alternatively, the adhesive may not completely dissolve, and may insteadsimply weaken, which may increase the flexibility or pliability of thesensor 1060 without allowing it to completely unroll. In the illustratedembodiment, the sensor 1060, in both its planar form (FIG. 16) and itsrolled form (FIG. 17), includes a flat or straight leading end 1068.However, the sensor 1060, in either or both of its planar form and itsrolled form, may include a beveled leading end such that the sensormimics the shape of the leading (sharp) end of an insertion needle. Inaccordance with its unique design, the sensor 1060 illustrated in FIGS.16 and 17 provides both strong resistance to buckling during sensorinsertion and patient comfort after insertion.

In other embodiments, the column strength of the sensor may not besufficient to completely prevent the possibility of buckling duringsensor insertion. There are many possible reasons for this. For example,the sensor may be designed to focus on softness and flexibility toprovide better comfort to the patient. To reduce the risk of buckling ofthe sensor during insertion, in some embodiments, a sheath may be usedto provide the sensor with additional column strength during insertion.

Furthermore, the sheath may be designed to be formed, at least in part(e.g., the intraluminal surface), of a material with properties thatreduce the risk of it damaging the membrane. Materials that may be usedinclude, but are not limited to, silicone rubber, polyurethane, nylon,for example, or any other material that will not cause (or merely causeinconsequential) damage to the membrane. In addition to providingadditional column strength, the sheath may also protect the membranefrom contact with and (shear forces exerted by) skin and/or tissue, asthe sensor slides past skin and/or tissue during deployment. In someembodiments, the intraluminal surface of the sheath is lubricous, i.e.,has a low coefficient of friction, thereby reducing friction that may bepresent during retraction of the sheath. This protects the membrane frompotential damage induced by tear and wear. The lubricious surface can becreated by topical coating and/or blending the base material of thesheath with surface modifying additive(s) such as silicone, fatty acids,fluorinated polymers (e.g., PTFE), or other similar materials.

With reference to FIG. 18, the sensor 1070 includes a retractableintroducer sheath 1072 that covers the membrane 1074 during theinsertion procedure. The introducer sheath 1072 not only protects themembrane 1074 during the insertion procedure, but also may support andprovide additional column strength to the sensor 1070 for increasedresistance to buckling. After insertion, the introducer sheath 1072 isretracted (FIG. 19), leaving the sensor 1070 with the uncovered membrane1074 implanted within the host's skin and underlying tissue.

With reference to FIG. 19, in the illustrated embodiment the sensor 1070includes a tissue piercing element 1076 having a diameter greater thanthat of the sensor body 1078. However, the relative dimensions of theillustrated components are only one example and are not limiting. Theintroducer sheath 1072 may have an outside diameter that issubstantially equal to or less than the diameter of the tissue piercingelement 1076. In alternative embodiments, a tissue piercing element maynot be provided. A length of the introducer sheath 1072 may besubstantially equal to, less than, or longer than the length of thesensor body 1078. As discussed above, following insertion of the sensor1070, the introducer sheath 1072 is withdrawn from the skin. Theintroducer sheath 1072 may be withdrawn into a mounting unit (notshown). For example, the mounting unit may include a pull tab that maybe manually (by the user) or automatically (by mechanical designtriggered by connection of the electronics unit to the mounting unit)activated to remove the sheath.

Often, a membrane that is unprotected can become damaged and/ordelaminated during sensor insertion. This can render the implantablesensor unusable. In some embodiments, the sensor is designed with aportion at the distal end that has a larger cross-sectional profile thanother portions of the sensor. With this configuration, a shieldingeffect is created, whereby the above-described portion at the distal endshields (partially or completely) other portions of the sensor fromhaving to contact tissue as the sensor slides past the tissue duringsensor insertion. In some embodiments, one or more regions of thesurface of the sensor body and/or the tissue piercing element maycomprise one or more recessed portions (e.g., cavities, indentations,openings, grooves, channels, etc.) configured to serve as reservoirs ordepots for holding bioactive agents. The recessed portions may be formedat any preselected location and have any preselected depth, size,geometrical configuration, and/or dimensions, in accordance with theintended application. Use of reservoirs or depots can increase theamount of bioactive agents the sensor is capable of carrying anddelivering. In further embodiments, the sensor body and/or the tissuepiercing element may be hollow with a cavity and connected via variouspassages with one or more openings on its surface, so that bioactiveagents can be released from the cavity via the openings. In someembodiments, the sensor body and/or the tissue piercing element maycomprise a pocket shaped and dimensioned to support a sensor with amembrane disposed thereon.

FIGS. 20-22 illustrate embodiments that incorporate the foregoingconcepts into their designs. As illustrated, each sensor 1080, 1082includes a cross-section that defines at least one recessed area ortrough that extends along the length of the sensor. With reference toFIGS. 20 and 21, the sensor 1080 defines a “plus sign” or x-shapedcross-section defining four evenly spaced troughs 1084 across the lengthof the sensor's longitudinal axis, except at the distal end 1085 (FIG.21). At the distal end 1085, the sensor 1080 comprises a plurality ofouter perimeter sections 1088 that provide the distal end of the sensor1080 with a larger cross-sectional profile than the rest of the sensor1080. With reference to FIG. 22, along its longitudinal axis, the sensor1082 defines a circular cross-section having a single trough or cutout1086, except at the distal end 1087 where there is no trough or cutoutand where the cross-section is completely circular. The troughs 1084,1086 may define spaces for disposing the electrodes, and the membranesthat cover the electrodes, such that the electrodes and membranes are atleast flush with or preferably recessed beneath an outer perimeter 1088,1090 of the sensor 1080, 1082. Recessing the electrodes and membranes(or locating them flush with the sensor outer perimeter) protects themembranes from damage from shearing forces caused by the host'sskin/tissue during the sensor insertion procedure by creating a spacingbetween the membranes and the host's skin and tissue. The troughs my notextend fully to the tip of the sensor body, to further protect themembranes during sensor insertion. After the sensor 1080, 1082 isinserted, settling/relaxation of the host's tissue increases the desiredcontact between the electrodes and the host's bodily fluids as neededfor proper sensor functioning. The cross-sectional shapes illustrated inFIGS. 20-22 are merely examples. The present embodiments include sensorsof any of a variety of cross-sectional shapes, including, withoutlimitation, any general polygon, a star (having any number of points), asquare, a pentagon, a heptagon, an octagon, an ellipse, or the like. Thepresent embodiments may have any number of troughs for locatingelectrodes, for example, one, two, three, five, nine, twelve, or more.

FIG. 23 illustrates another sensor 1102 configured for direct pressinsertion according to the present embodiments. The sensor 1102 of FIG.23 includes a protective sheath 1104 that covers the sensor 1102 duringthe insertion process. After the sensor 1102 is inserted, the sheath1104 is retracted partially or fully to expose the sensor 1102 and/orthe sensor tip 1106. Similar to the embodiment illustrated in FIG. 18,the protective sheath 1104 not only protects the membrane during theinsertion procedure, but also may provide additional column strength forincreased resistance to buckling. Furthermore, the sheath adds volumeand cross-sectional area to the sheath/sensor assembly. Thus, when thesheath is removed (partially or fully), a small spacing may be createdbetween the sheath and the surrounding tissue. This spacing then becomesoccupied by the surrounding tissue as the tissue moves toward thesensor. While not wishing to be bound by theory, it is believed that abetter tissue-sensor interface may be formed (for example, with lesstrauma, less inflammation, less risk of bleeding, etc.) when the tissuemoves toward and contacts the sensor, rather than the other way around.

FIG. 24 illustrates another sensor 1108 configured for direct pressinsertion according to the present embodiments. The sensor 1108 includesone or more through holes 1110, and the membrane(s) 1112 is/are disposedwithin the through holes 1110. In the illustrated embodiment, the sensor1108 includes a tissue piercing distal tip 1114, but in alternativeembodiments the tissue piercing distal tip 1114 may be omitted. In someembodiments, the through holes are shaped and dimensioned to enhancecertain sensor characteristics. Although the through holes 1110 shown inFIG. 24 are substantially circular, in some embodiments, the throughholes may be shaped or dimensioned differently. These differences maycause the electroactive surface in each of these through holes to behavedifferently and/or measure differently. For example, a deep through holemay contain a larger volume of interstitial fluid, compared to a shallowthrough hole. Accordingly, in some circumstances, the electrodecorresponding to the deep through hole may provide a bettersignal-to-noise ratio or some other characteristic. On the other hand,because the volume of water displaced in the shallow through hole is afaster turnover rate, the electrode corresponding to the shallow thoughhole may have less lag issues, which can be important when a patient'sanalyte concentration is changing rapidly. In other embodiments, theshapes and dimensions of the different through holes may be designeddifferently to measure different species. For example, one of thethrough holes may have a shape and/or dimension that differs fromanother and that allows its corresponding electrode to better measureoxygen, rather than a different analyte (e.g., glucose).

Instead of, or in addition to through holes, the sensor may include oneor more depressions 1118 in which the membrane(s) is/are disposed. Forexample, FIG. 25 illustrates another sensor 1116 configured for directpress insertion according to the present embodiments. The sensor 1116shown in FIG. 25 includes a plurality of depressions 1118, or dimples,or pores, or cavities, etc. (hereinafter referred to as depressions 1118for simplicity) in its outer surface. The depressions 1118 may bearranged in a pattern, or randomly arranged.

In some embodiments, the sensor 1116 may be covered by aparticle-containing membrane system that comprises a conductivecomponent dispersed in a non-conductive component (e.g., a polymermembrane material). The conductive component may comprise a plurality ofconductive particles dispersed through the membrane system, some ofwhich are covered at least in part by an enzyme material (e.g., glucoseoxidase) configured to produce a species that is measured by theconductive particles to produce a signal. The conductive particles maycomprise any of a variety of conductive, electroactive materials, suchas, for example, platinum, platinum-iridium, graphite, silver, silverchloride, carbon, and/or conductive polymers.

In other embodiments, at least one of the depressions 1118, such as someof the depressions 1118 or all of the depressions 1118, may containenzyme and/or membrane material. For example, the membrane may be flushwith an outer surface of the sensor 1116, or recessed beneath an outersurface of the sensor 1116. Recessing the membrane(s) (or locating themflush with the sensor 1116 outer surface) protects the membranes fromdamage from shearing forces caused by the host's skin/tissue during thesensor insertion procedure by creating a spacing between the membranesand the host's skin and tissue. After the sensor 1116 is inserted,settling/relaxation of the host's tissue increases the desired contactbetween the electrodes and/or membranes and the host's bodily fluids asneeded for proper sensor functioning. Alternatively, the membrane mayprotrude from the outer surface of the sensor 1116. The sensor 1116shown in FIG. 25 may further include an outer bioprotective layer (notshown) or a bio-interface layer formed of a hydrophilic material toallow for easy sensor insertion with low push forces and reducedfriction with surrounding tissue.

In some embodiments, the sensor may comprise a rigid outer layer thatprovides additional column strength to provide additional resistance tobuckling during sensor insertion.

FIG. 26 illustrates another sensor 1120 configured for direct pressinsertion according to the present embodiments. The sensor 1120 includesa plurality of axially spaced depressions 1122 configured for receivingenzyme and/or membrane material 1124. The sensor 1120 further includesan outer layer 1126 of a material that is permeable to one or moreselected analytes, including without limitation glucose. The outer layer1126 not only shields and protects the underlying sensor 1120/membrane1124 system during the sensor insertion procedure, but may also providehardness and/or increased column strength for resistance to bucklingduring insertion. Because the outer layer 1126 is very permeable to oneor more selected analytes, it does not have a substantial negativeimpact on the functionality of the sensor 1120.

Any of the embodiments described herein may incorporate an outer layer.Examples of materials for the outer layer 1126 include, withoutlimitation, non-glucose limiting hydrogel, a polymer and/or carbohydratefilm (e.g., a cellulose acetate film) or a metal film with micro porousstructures or micro channels that permit analytes (e.g., glucose) topass therethrough, or a lattice structure formed of metal or a hardpolymer and formed with openings sized to permit analytes to passtherethrough. Polymers and/or sugars that may be used include, withoutlimitation, cyanoacrylate polymers, polyurethanes, polyurethane urea,polyacrylates, polystyrene, polysulfone, polyetherketone, polycarbonate(e.g., polytrimethylcarbonate), polyimide, polyester, polyether,epoxide, maltose, PVP, polyethylene, L-lactide, or polycaprolactone.

As noted above, hardness of the outer layer 1126 may provide the sensorwith additional column strength and enhance its ability to protect themembrane. With respect to any of the sensors described in thisapplication that comprise an outer layer, the outer layer may be formedwith a material that has a hardness on the Shore A scale of from about30 to about 95, sometimes from about 70 to about 90, other times fromabout 50 to about 70.

FIG. 27 illustrates another sensor 1128 configured for direct pressinsertion according to the present embodiments. The sensor 1128 includesa sensor body 1130 with an overlying membrane 1132 and a protectiveouter layer 1134 disposed over the sensor 1128/membrane 1132 system. Theprotective outer layer 1134 not only shields and protects the underlyingsensor 1128/membrane 1132 system during the sensor insertion procedure,but may also provide hardness and/or stiffness for increased columnstrength and resistance to buckling during insertion. The protectiveouter layer 1134 may comprise a dissolving material, such as a polymer,for example and without limitation. In some embodiments, the protectivelayer is formed of a material that is in a rigid state when dehydratedand/or at room (or lower than room) temperature. In this rigid state,the protective layer protects the membrane from damage during insertionand also improves the column strength of the sensor, thereby enablinginsertion. When exposed to body temperature and/or hydration, theprotective layer becomes soft and flexible. In this state, theprotective outer layer provides the patient wearer with better comfort.Examples of dissolving and/or degradable polymers include, withoutlimitation, polyvinyl-pyrrolidone (PVP), polymerized sugar such ascaramel, polyvinyl acetate, polyethylene glycol, polyesters,polyaminoacid, polycarbonate, polyanhydride, polylactic acid,polyglycolic acid, polydioxanone, polyhydroxybutyrate,polyhydroxyvalerate, polycaprolactone, polyanhydrides (e.g., aliphaticpolyanhydrides in the back bone or side chains or aromaticpolyanhydrides with benzene in the side chain), polyorthoesters,polyaminoacids (e.g., poly-L-lysine, polyglutamic acid),pseudo-polyaminoacids (e.g., with back bone of polyaminoacids altered),polycyanocrylates, polyphosphazenes, and combinations or copolymersthereof and other similar polymers. Examples of non-polymeric dissolvingmaterials include, without limitation, sugars (e.g., maltose), liquidoleic acid, vitamin E, peanut oil, and cottonseed oil, and other similarcompounds. After the sensor 1128 is inserted and the protective outerlayer 1134 dissolves, the sensor 1128 becomes more flexible (compared tothe coated sensor 1128) for enhanced comfort of the host. Alternatively,the protective outer layer 1134 may comprise a material that does notcompletely dissolve, but rather softens after insertion into the host toenhance the comfort and wearability of the sensor 1128. Examples ofsoftening materials include, without limitation, hydrophilic polymers,shape memory polymers including, but not limited to polyurethanes,polyesters, polyamides, polycarbonate, polyether, polylactic acid,polyglycolic acid, polydioxanone, polyhydroxybutyrate,polyhydroxyvalerate, polycaprolactone, polyanhydrides, polyorthoesters,polyaminoacids, pseudo-polyaminoacids, polycyanocrylates, orpolyphosphazenes, and copolymers, blends, or combinations thereof andother similar polymers. The protective outer layer 1134 may be formed bydipping the sensor body 1130 and membrane 1132 in a liquid solution ofthe outer layer 1134 material, which subsequently solidifies andhardens. The dipping process may be tailored to produce a thinnercoating at the tip 1136 to aid insertion. The liquid solution may bereactive and non-reactive, the reactive solution may be further reactedto increase the protective strength and mechanical support forinsertion.

FIG. 28 illustrates another sensor 1138 configured for direct pressinsertion according to the present embodiments. The sensor 1138 includesan outer layer 1140 of a rigid or stiff material. The outer layer 1140covers substantially all of the sensor 1138, but includes at least oneopening or window 1142. The window(s) 1142 is/are located over theelectrodes such that the electrodes (and any membrane(s) overlying theelectrodes) are exposed for contact with the tissue and/or bodily fluidsof the host. The outer layer 1140 not only shields and protects theunderlying sensor 1138/membrane system during the sensor insertionprocedure, but may also provide hardness and/or increased columnstrength for resistance to buckling during insertion. Example materialsfor the outer layer 1140 include, without limitation, cyanoacrylatepolymers, polyurethanes, polyurethane urea, polyacrylates, polystyrene,polysulfone, polyetherketone, polycarbonate (e.g.,polytrimethylcarbonate), polyimide, polyester, polyether, epoxide,maltose, PVP, polyethylene, L-lactide, or polycaprolactone.

FIG. 29 illustrates another sensor 1144 configured for direct pressinsertion according to the present embodiments. The sensor 1144 includesa conductive wire 1146, which may comprise a metal or any otherconductive material. An outer coating 1148 is disposed over the wire1146. The outer coating 1148 may have a greater thickness than the wire1146. For example, the outer coating 1148 may be 1.5× thicker than thewire 1146, 2× thicker than the wire 1146, 2.5× thicker than the wire1146, 3× thicker than the wire 1146, 3.5× thicker than the wire 1146, orthe outer coating 1148 may have any thickness relative to the wire 1146.The outer coating 1148 may comprise a polymer such as, withoutlimitation, cyanoacrylate polymers, polyurethanes, polyurethane urea,polyacrylates, polystyrene, polysulfone, polyetherketone, polycarbonate,polyimide, polyester, polyether, epoxide, polytetrafluoroethylene, andcopolymers, combinations, or blends thereof.

The outer coating 1148 may include at least one opening or window 1150corresponding to a location (or locations) of the electrode(s). Forexample, the window(s) 1150 may be formed by ablation, such as by laserablation. Membrane 1152 may be disposed within the window(s) 1150, andmay be recessed beneath an outer surface of the outer coating 1148. Therecessed membrane 1152 is spaced from the host's skin and/or tissueduring the sensor insertion process, thereby protecting the membrane1152 from damage that could occur due to friction between the membrane1152 and the host's skin and/or tissue.

The sensor 1144 may further include a highly permeable outer layer 1154such as, without limitation, a hydrogel, overlying the membrane 1152 inthe area(s) of the window(s) 1150. The highly permeable outer layer 1154provides a mechanical buffer against damage to the membrane 1152 and/orelectrode(s) located beneath the highly permeable outer layer 1154.

Advantageously, the sensor 1144 of FIG. 29 enables, but does notrequire, reel-to-reel continuous processing. Also, if desired, theentire sensor 1144 assembly, including all or some of the componentsshown in FIG. 29, can be further processed with laser ablation and/or amechanical die to remove any excess material and/or to create a freshedge to face the host's tissue.

FIG. 30 illustrates another sensor 1156 configured for direct pressinsertion according to the present embodiments. The sensor 1156 includesa membrane 1158 that is only applied in one or more regions of thesensor 1156. The membrane 1158 may be flush with an outer surface 1160of the sensor 1156, recessed beneath the outer surface 1160 of thesensor 1156, or protruding from the outer surface 1160 of the sensor1156. In embodiments in which the membrane 1158 is flush with orrecessed beneath the outer surface 1160 of the sensor 1156, the membrane1158 may be located within one or more openings or windows in the outersurface 1160 of the sensor 1156. The membrane 1158 may be applied to thesensor 1156 according to any desired process, such as printing andlithographic processing where the deposit of the membrane can be sitespecific. In some embodiments, printing is preferable, because itpermits a very localized, controlled membrane deposition.

The outer surface 1160 of the sensor 1156 of FIG. 30, in areas otherthan the membrane 1158, may comprise a polymer, such as, withoutlimitation, polytetrafluoroethylene (PTFE), cyanoacrylate polymers,polyurethanes, polyurethane urea, polyacrylates, polystyrene,polysulfone, polyetherketone, polycarbonate, polyimide, polyester,polyether, epoxide, and combinations, blends, or copolymers thereof. Thedistal end of the polymer may include a piercing tip 1162 configured topenetrate skin and/or tissue, and which has properties desirable forinsertion. This sensor 1156 of FIG. 30 advantageously simplifiesprocesses for making the sensor 1156 by not “dulling” the distal tip1162 by applying membrane 1158 to the tip 1162. This sensor 1156 of FIG.30 advantageously can be used in combination with other modes ofmembrane protection, such as any of the embodiments described elsewhereherein.

Manufacturing Techniques

One aspect of the present embodiments includes the realization that thematerials used to form the membranes of analyte sensors are often soft,and thus tend to delaminate (i.e., peel back and sometimes peel off) asthe sensor advances into skin and/or tissue. This problem is especiallyacute for sensors formed by a process in which the sensors are firstcoated with a membrane and then sharpened at the tip. This processexposes the sensor body, and leaves a thin coating of the membranesurrounding the sides of the sensor body at the tip. Some of the presentembodiments provide solutions to this problem, including how to form thetip after applying the membrane, without damaging the tip, and whilestill maintaining the integrity of the tip.

With respect to sensor manufacturing, two approaches relate to whetherthe membrane coating step should precede the sharpened tip formationstep, or whether the sharpened tip formation step should precede themembrane coating step. With the first approach, the membrane is coatedonto the sensor workpiece prior to formation of the sharpened distaldip. With this first approach, the technical challenges involve findingtechniques that permit creation of the sharpened tip, without causingdamage to the membrane, and/or without creating excess membrane at thetip.

With reference to FIGS. 30A and 30B, in one method that adopts the firstapproach, a membrane 1161 is coated onto a sensor workpiece 1163. Insome instances involving dipping, a bead 1165 (FIG. 30A) may form at oneend of the workpiece 1163. Laser ablation, or mechanical cutting orgrinding, for example, is then used to sharpen the distal end of theworkpiece 1163 into a tip 1167 (FIG. 30B). By doing so, the bead 1165 onthe distal end of the workpiece 1163 is removed. In the illustratedembodiment, sharpening the distal end of the workpiece 1163 comprisesremoving material from only one side of the workpiece 1163, thus forminga tip 1167 having a shape similar to a hypodermic needle point. Inalternative embodiments, material may be removed from two opposite sidesof the workpiece 1163 to form a wedge-shaped tip. In still furtheralternative embodiments, material may be removed from the workpiece 1163about a full 360° to form a cone-shaped tip.

FIGS. 31-33 illustrate another process for making a sensor that adoptsthe first approach. With reference to FIG. 31, a conductive wire 1164includes a membrane coating 1166. The wire 1164 may be a metal, such asand without limitation, tantalum, platinum, stainless steel,platinum-iridium, silver, silver chloride, palladium, or any othermetal.

The process of FIGS. 31-33 may include a step of applying the membrane1166 to the wire 1164, or the process may commence with the wire 1164already having been coated with the membrane 1166. An annular channel1168 is then formed about the entire circumference of the coated wire1164. The channel 1168 extends through the membrane 1166 and partiallyinto the wire 1164. The channel 1168 may be formed by any process, suchas mechanical cutting, grinding, laser ablation, heating, etc. In theillustrated embodiment, the channel 1168 has a v-shaped cross-section,but the channel 1168 may have any of a variety of cross-sectionalshapes. This process has been found to prevent the membrane fromcovering the distal tip, which is advantageous, because in otherprocesses membrane must be subsequently removed from the tip, which addsanother process step.

With reference to FIG. 32, tension is applied to the coated wire 1164,either subsequent to the channel 1168 being formed, or simultaneouslytherewith. The tension induces strain in the wire 1164 in the region ofthe channel 1168, causing the wire 1164 to neck and eventually fracture.The necking process produces a sharp tip 1170 at the end of each of thetwo severed wire pieces 1164, and each of the sharp tips 1170 comprisesthe conductive wire material 1164, which may be a metal. In someembodiments, in addition to subjecting the channel 1168 of the wire 1164to tension, the channel 1168 may also be subjected to heating. During orafter the necking process, in some instances, the tips 1170 may be in asoft and/or malleable condition. In some embodiments, the surface of thetip may be subjected to further mechanical processing (e.g., through useof a sharpener, grinder, mold, etc.) to shape the distal tip so that itis sharp. The sharp tips 1170 advantageously can be used to pierce skinand/or tissue during the sensor insertion process.

With reference to FIG. 33, the sharp tips 1170 formed as a result ofpulling the coated wire 1164 apart may subsequently be covered with aprotective outer layer 1172 to protect the exposed conductive wire 1164and/or the membrane 1166. The protective outer layer 1172 may comprise,for example and without limitation, a hardened polymer, such ascyanoacrylate polymers, polyurethanes, polyurethane urea, polyacrylates,polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide,polyester, polyether, epoxide, polytetrafluoroethylene, and copolymers,combinations, or blends thereof. In addition, the protective outer layer1172 may comprise any other protective layer materials described hereinor elsewhere and also possess the mechanical properties described hereinwith respect to a protective outer layer. The protective outer layer1172 may be applied with any process, such as solution-based coatingwhere the reactive monomers and/or oligomers or non-reactive polymer arepre-dissolved, mixed or dispersed, extrusion, or printing, or any otherprocess described herein or elsewhere related to coating.

Sensors formed by the process of FIGS. 31-33 advantageously include asharp tip 1170 that can be used to pierce skin and/or tissue during thesensor insertion process. In certain embodiments, the membrane 1166preferably does not overlap the sharp tip 1170 to avoid dulling the tip1170, which, in turn, would render the tip 1170 less effective forpiercing skin and/or tissue.

FIG. 34 corresponds to another process for making a sensor that adoptsthe first approach described above, in which the membrane is coated ontothe sensor workpiece prior to formation of the sharpened distal dip. Theprocess includes wire stock 1174 having a membrane coating 1176. Thewire stock 1174 may be a material that is nonconductive andnon-electroactive, such as and without limitation, polyurethanes,polyurethane urea, polyacrylates, polystyrene, polysulfone,polyetherketone, polycarbonate, polyimide, polyester, polyether,polyamide, and blends, combinations, or copolymers thereof. The processof FIG. 34 may include a step of applying the membrane 1176 to the wirestock 1174, or the process may commence with the wire stock 1174 alreadyhaving been coated with the membrane 1176.

The wire stock 1174 shown in FIG. 34 is wound on a reel 1178, and theprocess of FIG. 34 is well suited for use in a continuous reel-to-reelprocess. However, the reel 1178 shown in FIG. 34 is just one example andis not limiting.

In the process of FIG. 34, the entire length of wire stock 1174 iscoated with the membrane 1176. Portions of the membrane 1176 are thenselectively removed at spaced locations along the wire stock 1174 as thewire stock 1174 is unwound from the reel 1178. The membrane 1176 may beremoved at various locations in relation to the finished sensor, such asat the tip and/or at any other locations along the length of thefinished sensor. In one non-limiting example, the membrane 1176 may beremoved with a laser 1180 in a laser ablation process. After certainportions of membrane 1176 are removed, the wire stock 1174 is singulatedat spaced locations to form a plurality of membrane-coated sensor wires.The membrane-coated sensor wires advantageously have no membrane 1176 atthe sensor tip, where the membrane 1176 could blunt the tip and make thetip unsuitable for piercing skin and/or tissue.

In an alternative process, the singulation step itself may removemembrane 1176 from the sensor tip. Thus, for example, no separate step(besides singulating) may be performed to remove the membrane 1176 fromthe sensor tip. In yet another alternative process, the membrane removaland singulation steps may be performed as described above, but the wirestock 1174 may comprise a conductive material, such as a metal. Aftersingulation, another material, such as a polymer cap or second coating,may then be applied to cover the sensor tip to prevent the tip fromgenerating background signal when the sensor is inserted in the host.

There is a need for an implantable sensor that incorporates a layer ofrigid material in the distal end of the sensor to not only protect theunderlying membrane or to increase the sensor's column strength, asdescribed elsewhere herein, but to inhibit shifting of the sensormembrane during sensor insertion. A typical sensor membrane is fragileand may be displaced during the process of sensor insertion, causingpoor sensor performance. It is preferable for the sensor to remain inplace on the sensor wire with little to no mechanical displacementrelative to the sensor wire. Shifting of the membrane can cause themembrane to no longer cover the electrode(s). Similarly, in extremecases, the membrane may become completely delaminated from the sensor.In addition, the sensor tip may be exposed before or during theinsertion process, potentially generating background signal and/orcausing variable sensor sensitivity. Further, it is sometimes desired togrind or otherwise process the tip of the sensor after the membrane hasbeen applied. The grinding or other processing may expose the sensorwire, which can also generate background signal and/or cause variablesensor sensitivity. With reference to FIGS. 35-37, a process for makinga sensor adopts the first approach described above of coating themembrane onto the sensor workpiece prior to forming the sharpened distaldip. The process involves a conductive wire 1182 having a membranecoating 1184. The wire 1182 may be a conductive material, including, butnot limited to any conductive material disclosed elsewhere herein. In analternative embodiment, a process similar to that shown in FIGS. 35-37may involve a bare wire 1182 (i.e., with no membrane thereon) and a stepof applying the membrane 1184 to the wire 1182. With reference to FIG.36, a distal end 1186 of the membrane-coated wire 1188 is ground toproduce a sharp tip 1190. Alternatively, the sharp tip 1190 may beproduced by processes other than grinding, including any othersharpening, cutting, or singulating techniques disclosed herein orelsewhere. Through grinding or other processing, the distal end 1192 ofthe sensor wire 1182 is exposed.

With reference to FIG. 37, a coating 1192 is applied over the distal end1186 of the membrane-coated wire 1188. The coating 1192 may be, forexample, and without limitation, a hard polymer such as cyanoacrylate,or cyanoacrylate polymers, polyurethanes, polyurethane urea,polyacrylates, polystyrene, polysulfone, polyetherketone, polycarbonate,polyimide, polyester, polyether, epoxide, or any other material(s)capable of preventing detectable membrane movement during sensorinsertion. The coating 1192 may be applied by any desired process, suchas, and without limitation, dip coating, spraying, vapor deposition,extrusion, molding, or printing. The coating 1192 advantageously createsan impermeable barrier on the exposed end surface 1192 of the conductivesensor wire 1182, rendering the end surface 1192 non-electroactive, andtherefore not capable of producing background signal or causing variablesensor sensitivity. The coating 1192 may also permeate into the membrane1184 to harden or stiffen the membrane 1184 and cause it to more firmlyadhere to the wire 1182, making the membrane 1184 more mechanicallystable.

As noted above, with respect to sensor manufacturing, two approachesrelate to whether the membrane coating step should precede the sharpenedtip formation step, or whether the sharpened tip formation step shouldprecede the membrane coating step. With the first approach, which isdescribed above, the membrane is coated onto the sensor workpiece priorto formation of the sharpened distal dip. With a second approach, theworkpiece is formed with a sharpened distal tip prior to the membranecoating process. With the second approach, one common technicalchallenge involves impeding or preventing membrane material from coatingthe sharpened distal tip and thereby dulling the tip, which in turnmakes it more difficult (or more painful) for sensor insertion.

In some embodiments, materials (e.g., membrane or outer layer material)are coated onto a sensor workpiece (e.g., a sensor wire) using a dippingtechnique, wherein the sensor workpiece is dipped into a solutioncomprising a material that is to form a film or layer over theworkpiece. Often, the distal end of the workpiece is the portion of theworkpiece that is dipped first, because during the dipping process it isdisposed at a lower vertical position than other portions of theworkpiece. Because of gravity, the applied coating will typically sagtoward the lowest end (i.e., the distal end) of the sensor workpiece,resulting in dulling of the distal tip, which in some embodiments isused to pierce skin and/or tissue. While not wishing to be bound bytheory, it is believed that, holding everything else equal, with acoating formed from a low viscosity solution, the gravity-inducedsagging issue may be worse, as compared to a high viscosity solution.

FIGS. 38 and 39 illustrate a process designed to overcome thesetechnical challenges. With reference to FIG. 38, the process includes asensor wire 1194 having a sharp distal tip 1196. The sensor wire 1194 isdipped, tip side down, in a membrane solution to form a membrane 1198 onthe sensor wire 1194. After the membrane solution dries, a portion ofthe solidified membrane 1198 is removed at the distal end 1200 of thesensor wire 1194, as shown in FIG. 39. The membrane 1198 may be removedusing any of a variety of processes, such as and without limitation,laser ablation, electropolishing, bead blasting, dry ice blasting,burning, or any other process. After the membrane 1198 is removed fromthe distal end 1200 of the sensor wire 1194, the exposed portion 1202 ofthe sensor wire 1194 may be coated with a protective layer (not shown),such as a hard polymer. Example materials for the protective layerinclude without limitation, cyanoacrylate polymers, polyurethanes,polyurethane urea, polyacrylates, polystyrene, polysulfone,polyetherketone, polycarbonate, polyimide, polyester, polyether,epoxide, and any other materials disclosed herein or elsewhere used toform the protective layer.

FIGS. 40 and 41 illustrate another process for removing membranematerial from the distal end of the sensor wire. With reference to FIG.40, the sensor 1204 has been dipped in a membrane solution, and thestill wet solution 1206 forms a bead 1208 at the distal end 1210 of thesensor. With reference to FIG. 41, the distal end 1210 may be blotted orwiped with a fibrous body 1212 while the membrane solution 1206 is stillwet. Some of the membrane solution 1206 at the distal end 1210 of thesensor 1204 is absorbed by the fibrous body 1212, as shown in FIG. 41.The fibrous body 1212 may comprise, for example and without limitation,a cloth, a cotton swab, a wicking pad, a sponge, etc. In anotherembodiment, instead of absorbing the excess membrane coating at thedistal end, a tip may be used to contact the bead 1208 to break itssurface tension, thereby causing some (if not all) of the excessmembrane coating to drip off the distal tip. In certain embodiments,this procedure can be performed in conjunction with the above-describedprocesses for absorbing excess membrane coating.

FIGS. 42 and 43 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. With reference to FIG. 42, the process includes a wire 1214having a membrane coating 1216. The wire 1214 may be a conductivematerial, such as a metal, such as and without limitation, tantalum,platinum, or any other material described herein or elsewhere for use asa conductive and/or electroactive metal. The process of FIGS. 42 and 43may include a step of applying the membrane 1216 to the wire 1214, orthe process may commence with the wire 1214 already having been coatedwith the membrane 1216. The membrane 1216 may comprise a single layer,or a plurality of layers 1218 as illustrated.

With reference to FIG. 43, an end cap 1220 is applied to the tip of themembrane-coated wire 1214. The end cap 1220 comprises a material that isrigid, and preferably resistant to biofouling (e.g., resistant toprotein adhesion to the membrane, which can reduce the membrane'spermeability to analyte), and that can be formed or machined. Examplematerials include, without limitation, polytetrafluoroethylene (PTFE),cyanoacrylate polymers, polyurethanes, polyurethane urea, polyacrylates,polystyrene, polysulfone, polyetherketone, polycarbonate, polyimide,polyester, polyether, epoxide. The end cap 1220 may be applied to thesensor via any desired process, such as coating, injection molding, ormechanical interlocking from a preformed tip made from polymer or metal.The end cap 1220 may include a pointed tip 1222, or may be processed toproduce a pointed tip 1222. The pointed tip 1222 is configured forpiercing skin and/or tissue so that the sensor is configured for directpress insertion. The end cap 1220 advantageously facilitates directpress insertion while at the same time covering the distal end of thesensor wire 1214 so that it is not electroactive. The end cap 1220 mayalso provide a barrier that shields the distal end of the membrane 1216,making the membrane 316 less likely to be displaced from the end of thesensor wire 1214.

FIGS. 44 and 45 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. With reference to FIG. 44, the process includes a wire 1224having a membrane coating 1226. The wire 1224 may be a conductivematerial, such as a metal, such as and without limitation, tantalum,platinum, silver, silver chloride, and any other conductive metaldescribed herein or elsewhere. The membrane 1226 may include more thanone layer 1228, such as two layers, three layers, four layers, fivelayers, or any number of layers. The process of FIGS. 44 and 45 mayinclude a step of applying the membrane 1226 to the wire 1224, or theprocess may commence with the wire 1224 already having been coated withthe membrane 1226. Applying the membrane 1226 to the wire 1224 maycomprise printing, coating, vapor deposition, extrusion, or any otherprocess described herein or elsewhere for coating a material onto asensor workpiece. And, in the case of a multilayer membrane 1226, theprocess for forming each layer 1228 may be repeated any number of timesuntil the desired number of layers is achieved. And, at least one layer1228 of the multilayer membrane 1226 may be formed by a process that isdifferent from a process or processes used to form at least one otherlayer 1228.

With further reference to FIG. 44, a rigid coating 1230 is formed at thetip of the sensor over the membrane 1226. The rigid coating 1230 maycomprise cyanoacrylate polymers, polyurethanes, polyurethane urea,polyacrylates, polystyrene, polysulfone, polyetherketone, polycarbonate,polyimide, polyester, polyether, polyamide, epoxide, or any other rigidpolymers described herein or elsewhere for forming an outer layer (e.g.,a protective outer layer). A process for forming the rigid coating 1230may comprise solution based coating, extrusion, or molding, or any otherprocess described herein or elsewhere for coating a material onto asensor workpiece.

With reference to FIG. 45, the rigid coating 1230 is shaped to produce apointed tip 1232. The pointed tip 1232 is configured for piercing skinand/or tissue so that the sensor is configured for direct pressinsertion. The rigid coating 1230 with pointed tip 1232 advantageouslyfacilitates direct press insertion while at the same time covering thedistal end of the sensor wire 1224 so that it is not electroactive. Therigid coating 1230 also provides a barrier that shields the distal endof the membrane 1226, making the membrane 1226 less likely to bedisplaced from the end of the sensor wire 1224.

FIGS. 46-48 illustrate another process for making a sensor configuredfor direct press insertion according to the present embodiments. Asensor produced according to the process of FIGS. 46-48 advantageouslydoes not expose the end of the sensor wire, such that the sensor wire atthe tip is not electroactive and does not produce background signal ornegatively affect the sensitivity of the sensor. With reference to FIG.46, the sensor 1234 includes a sensor body 1236 and a piercing tip 1238.The tip 1238 includes a substantially triangular cross-section with apointed distal end 1240. A proximal end 1242 of the tip 1238 defines adiameter that is greater than a diameter of the sensor body 1236.However, the illustrated shape of the sensor 1234 is just one exampleand is not limiting.

With further reference to FIG. 46, a membrane 1244 is applied to thesensor 1234, including the sensor body 1236 and the piercing tip 1238.The membrane 1244 may be applied by any desired method, such as dipcoating, spray coating, brush coating, printing, extrusion, or any othermethod described herein or elsewhere for coating a membrane onto asensor workpiece (e.g., sensor body). With reference to FIG. 47, acoating 1246 is applied to the piercing tip 1238 of the sensor 1234. Thecoating 1246 prevents the piercing tip 1238 from functioning as anelectroactive surface. In some embodiments, the coating 1246 maycomprise a material (e.g., silicone) that prevents a certain analyte(e.g., glucose) from passing therethrough. In other embodiments, thecoating 1246 may comprise a material that inactivates the membrane 1244,for example, by denaturing the enzyme in the membrane 1244 needed forgenerating a signal. The coating 1246 may be applied by any desiredmethod, such as any of the methods described herein or elsewhere forcoating a material onto a workpiece. In yet other embodiments, insteadof applying a coating 1246, the membrane 1244 may be inactivated by alight source or a heat source that can be used to denature the enzyme inthe membrane 1244.

With reference to FIG. 48, a retractable introducer sheath 1248 isapplied around the sensor body 1236. An outer diameter of the introducersheath 1248 is substantially equal to, or less than, the diameter of thepiercing tip 1238 at its proximal end 1242. The introducer sheath 1248covers and protects the membrane 1244 during the sensor insertionprocedure, making it less likely that the membrane 1244 will bedisplaced or damaged.

FIGS. 49-51 illustrate another process for making a sensor configuredfor direct press insertion according to the present embodiments. Asensor produced according to the process of FIGS. 49-51 advantageouslydoes not expose the end of the sensor wire, such that the sensor wire atthe tip is not electroactive and does not produce background signal ornegatively affect the sensitivity of the sensor. With reference to FIG.49, the sensor 1250 includes a sensor body 1252, and a membrane 1254 isapplied to the sensor body 1252. The sensor body 1252 may be aconductive material, such as a metal, such as and without limitation,tantalum, platinum, or any other conductive metal disclosed herein orelsewhere. The membrane 1254 may be applied by any desired method, suchas dip coating, spray coating, brush coating, printing, extrusion,and/or combinations thereof.

With reference to FIG. 50, a piercing tip 1256 is applied to the distalend of the sensor body 1252. The tip 1256 may be formed in a separateprocess, or formed as part of the same process for forming the sensorbody 1252. The tip 1256 may be attached to the distal end of the sensorbody 1252 by any desired process, such as mechanical crimping, pressfitting, welding (such as ultrasonic welding), shrink tubing,application of heat, etc. The tip 1256 may comprise the same material asthe sensor body 1252, or a different material. For example, the tip 1256may be conductive, such as metallic, or non-conductive, such asnon-metallic. Example materials for the tip 1256 include, withoutlimitation, cyanoacrylate polymers, polyurethanes, polyurethane urea,polyacrylates, polystyrene, polysulfone, polyetherketone, polycarbonate,polyimide, polyester, polyether, polyamide, and epoxide.

The tip 1256 includes a substantially triangular cross-section with apointed distal end 1258. A proximal end 1260 of the tip 1256 defines adiameter that is greater than a diameter of the sensor body 1252.However, the illustrated shape of the sensor 1250 is just one exampleand is not limiting.

With reference to FIG. 51, a retractable introducer sheath 1262 isapplied around the sensor body 1252. An outer diameter of the introducersheath 1262 is substantially equal to, or less than, the diameter of thepiercing tip 1256 at its proximal end 1260. The introducer sheath 1262covers and protects the membrane 1254 during the sensor insertionprocedure, making it less likely that the membrane 1254 will bedisplaced or damaged. The introducer sheath 1262 may be metallic ornon-metallic, for example. A non-metallic sheath may be made from, forexample and without limitation, polyolefin, polyurethanes, polyurethaneurea, polyacrylates, polystyrene, polysulfone, polyetherketone,polycarbonate, polyimide, polyester, polyether, polyamide, epoxide, orany other material.

The process of FIGS. 49-51 advantageously maintains sharpness of thepiercing tip 1256 by not applying membrane 1254 to the tip 1256. And,because there is no membrane 1254 on the piercing tip 1256, it is lesslikely that the membrane 1254 will be breached and/or delaminate duringthe sensor insertion process.

FIG. 52 illustrates another process for making a sensor configured fordirect press insertion according to the present embodiments. The sensor1264 includes a sensor body 1266, a membrane 1268 over the sensor body1266, and a sharp distal tip 1270 applied over the membrane 1268. Thetip 1270 may be formed by any process, such as and without limitation,dipping, adhering, melting/cooling, solvent cast/drying, molding (e.g.,extrusion or injection molding, press molding, or polymerizing in-situin a mold), machining of a substrate piece, 3-D printing, casting,sintering, forging, machining, or other known methods of manufacturingimplantable devices. In some embodiments, the material of the tip 1270may comprise, for example, and without limitation, abiodegradable/bioabsorbable material. Example materials include, withoutlimitation, polymers such as polyvinylpyrrolidone (PVP) and/or polyvinylalcohol (PVA), sugars such as maltose, and others.

The process of FIG. 52 advantageously creates a sharp tip 1270 after themembrane 1268 has been applied to the sensor body 1266. Thus, nomembrane 1268 is applied over the sharp tip 1270, which could dull thetip 1270. Another advantage, with respect to embodiments having a tip1270 comprising a material that is biodegradable/bioabsorbable, iscomfort of the host, since the tip 1270 dissolves after insertion. Usinga biodegradable/bioabsorbable tip can avoid the potential of leaving thetip inside the body, if the tip becomes detached from the sensor.

One aspect of the present embodiments includes the realization thatapplying a membrane to a sharp sensor tip presents challenges. Forexample, the sharp tip can breach the membrane and/or cause the membraneto delaminate, particularly when the sensor is subjected to frictionalforces during the process of sensor insertion. Also, applying a membraneto a sharp sensor tip may dull the tip, rendering the tip less effectivefor direct press insertion of the sensor. Some of the presentembodiments provide solutions to these problems, including how to applythe membrane to a sharp tip, without damaging the tip, and whilemaintaining the integrity of the tip.

FIG. 52A corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. Thesensor 1269 includes a core wire 1271, and an electrically insulativelayer 1273 over the core wire 1271. The insulative layer 1273 includes agap 1275 that exposes a portion of the core wire 1271 just proximal ofthe distal tip 1277. A conductive layer 1279 is disposed over theinsulative layer 1273 proximal of the gap 1275, but not distal of thegap 1275. The conductive layer 1279 may comprise for example, andwithout limitation, silver chloride. A membrane coating 1281 covers theconductive layer 1279, the exposed portion of the core wire 1271, andthe portion of the insulative layer 1273 distal of the gap 1275. Thedistal tip 1277 of the core wire 1271 is sharpened prior to applicationof the membrane coating 1281.

FIG. 53 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. Thesensor 1272 includes a sensor body 1274 having a core 1276 and an outerlayer 1278, and a membrane 1280 applied over the outer layer 1278, butnot over the core 1276. The core 1276 and the outer layer 1278 comprisedifferent materials. The core 1276 comprises a material that is rigidenough to form a piercing tip 1282, and may comprise a material thatdoes not necessarily adhere well to (or even repels) the membrane 1280.For example, the material of the core 1276 may have a low surface energyand be non-wetting. By contrast, the outer layer 1278 comprises amaterial to which the membrane 1280 readily adheres.

Example materials for the core 1276 include, without limitation,stainless steel, titanium, tantalum and/or a polymer, and the firstlayer may comprise platinum, platinum-iridium, gold, palladium, iridium,graphite, carbon, a conductive polymer, and/or an alloy. Alternatively,the core 1276 may comprise a material that is pretreated or coated withanother material that repels coating of the membrane 1280. Examplematerials for the pretreated core 1276 include, without limitation,materials that discourage the formation of films, such aspolytetrafluoroethylene. The pretreatment may comprise, for example, andwithout limitation, engineering the surface of the core 1276 tofacilitate breaking up of film. Alternatively, the pretreatment maycomprise a coating with a hydrophobic substance (e.g., asuperhydrophobic material), if the portion of the coated membrane firstdeposited, is hydrophilic, or conversely a coating with a hydrophilicsubstance (e.g., a superhydrophilic material), if the portion of thecoated membrane first deposited, is hydrophobic. The hydrophobicity of asurface can be measured by its contact angle with water. The greater thewater contact angle, the higher the hydrophobicity of the surface.Generally, if the water contact angle is smaller than 90°, the surfaceis considered hydrophilic, and if the water contact angle is larger than90°, the surface is considered hydrophobic. In some embodiments, thesurface of the pretreated core 1276 is hydrophobic and has a contactangle greater than about 120°, sometimes greater than about 135°, andsometimes greater than about 160°. In some embodiments, the surface ofthe pretreated core 1276 is hydrophilic and has a contact angle lessthan about 60°, sometimes less than about 45°, and sometimes less thanabout 30°.

Example materials for the membrane material include, without limitation,any material that may be used to form a membrane on an analyte sensor.Membrane materials that may be used include, but are not limited to,those described in U.S. Patent Publication No. 2009-0247856-A1, which isincorporated by reference herein in its entirety. The membrane describedin U.S. Patent Publication No. 2009-0247856-A1 may also be used to forma membrane on any of the sensors described herein.

In the process corresponding to FIG. 53, the outer layer 1278 and/ormembrane 1280 may be applied to the core 1276 or the sensor body 1274 byany of a variety of coating techniques, such as, for example, dipping,spraying, electro-depositing, dipping, casting, or a combination ofthese techniques. In some embodiments, the core 1276 may be advancedthrough a series of stations with any of a variety of other transportmechanisms, such as, for example, a robotic system, a conveyor system,and other like systems. These other transport mechanisms may be used incombination with (or as an alternative to) a reel-to-reel system. Forexample, in one embodiment, a reel-to-reel system is used to move thecore 1276 in the form of an elongated body, before it is singulated intoindividual workpieces, and a robotic system is used to move theindividual workpieces after the singulation process. Processes that maybe used to apply the outer layer and/or membrane include, but are notlimited to, those described in U.S. Patent Publication No.2011-0027458-A1, which is incorporated by reference herein in itsentirety.

The sharp distal tip 1282 may be formed by any of a variety oftechniques, such as, for example and without limitation, cutting bymechanical grinding, diamond wire, high-speed milling, abrasive waterjet cutting, electric discharge machining by wire or plunge,electrochemical etching, electrochemical polishing, electrochemicalmachining, stamping, laser cutting, or any other methods for cuttingand/or shaping a workpiece. In certain embodiments, the sharp distal tip1282 is formed by electrochemical grinding, which is a process thatremoves electrically conductive material by grinding with a negativelycharged abrasive grinding wheel, an electrolyte fluid, and a positivelycharged workpiece (which in this case is the sensor 1272). Materialremoved from the workpiece remains in the electrolyte fluid, which mayremove residual coatings formed on the surfaces of the sharpened distaltip. The techniques described above (e.g., electrochemical etching,electrochemical grinding) may also be used to form a sharp distal tip onany of the sensors described herein.

FIGS. 54 and 54A correspond to another process for making a sensorconfigured for direct press insertion according to the presentembodiments. The sensor 1284 includes a sensor body 1286 and a membrane1288 applied over the sensor body 1286. With reference to FIG. 54A, themembrane 1288 comprises a plurality of layers 1290, wherein a thicknessof each layer 1290 is less than a thickness of a typical single-layermembrane, but the thickness of the aggregated layers 1290 issubstantially equal to a thickness of a typical single-layer membrane.For example, the membrane 1288 may comprise two layers 1290, or threelayers 1290, or four layers 1290, or any other number of layers 1290. Athickness of each layer 1290 may be from about 0.5 microns to about 10microns, sometimes from about 1 micron to about 5 microns, or any otherthickness suitable for application in an implantable analyte sensor. Athickness of the layers 1290 may vary, wherein one or more of the layers1290 are thicker or thinner than other layers 1290. In the processcorresponding to FIGS. 54 and 54A, applying the membrane layers 1290 tothe sensor body 1286 may comprise any of a variety of coatingtechniques, such as, for example, printing, dipping, extrusion,spraying, electro-depositing, casting, or combinations thereof.

FIGS. 55 and 56 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. With reference to FIG. 55, the sensor 1292 includes asensor body 1294 with a sharp distal tip 1296. A membrane 1298 isapplied over the sensor body 1294 and the tip 1296. Then, with referenceto FIG. 56, the membrane 1298 is removed from the tip 1296, but not fromthe sensor body 1294. The membrane 1298 may be removed using anyprocess, such as, without limitation, etching (e.g., dry, wet,reactive-ion, and/or chemical etching), laser ablation, mechanicalstripping (such as abrading), UV light, or any other process forremoving polymer material from a substrate.

FIGS. 57 and 58 illustrate another process for making a sensor 1300configured for direct press insertion according to the presentembodiments. With reference to FIG. 57, the sensor 1300 includes asensor body 1302 with a sharp distal tip 1304. A membrane 1306 isapplied over the sensor body 1302 and the tip 1304 by dipping in amembrane solution 1308. Due to gravity, the deposited membrane 1306forms a “bead” in the area of the distal tip 1304. This geometry istypical when a membrane is applied with a dipping process, particularlywhen the membrane solution has a certain viscosity. In certaininstances, the bead of membrane 1306 material over the distal tip 1304disadvantageously dulls the tip 1304. Thus, with reference to FIG. 58,the process includes a step of dipping the membrane-covered distal tip1304 in a solvent 1310 to dissolve the membrane 1306 and substantiallyremove the membrane 1306 material from the sharp tip 1304 of the sensor1300. The solvent 1310 may comprise, for example, and withoutlimitation, tetrahydrofuran (THF), dimethylacetamide (DMAC),hexafluoroisopropanol, methylene chloride, methanol, methylethylketone,toluene, and dimethyl formamide. In some embodiments, the distal beadcan also be avoided by removing the excess material at the tip beforesolidifying via wiping, blowing, etc.

FIG. 59 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. Thesensor 1312 includes a sensor body 1314 with a sharp distal tip 1316. Amembrane 1318 is applied over the sensor body 1314 and the tip 1316 bydipping in a membrane solution (not shown). Then, before the membranesolution dries, the tip 1316 is dipped in a release agent 1320 thatprevents the membrane 418 from adhering to the tip 1316. The releaseagent 1320 may comprise, for example, and without limitation, silicone,petroleum oil, fluorinated compounds (e.g., tetra fluoroethylene-perfluoro alkylvinyl ether copolymer or perfluoroalkoxy),polytetrafluoroethylene, polyimide, polyetherimide, polyethersulfide,glycerin, or the like.

FIG. 60 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. Thesensor 1322 includes a sensor body 1324 with a sharp distal tip 1326.The sharp tip 1326 is coated with a sacrificial material 1328 thatprotects the tip 1326 during a subsequent step of applying a membrane1330 to the sensor 1322, and that is later removed, as described below.The sacrificial material 1328 may any of a variety of materials thatallows for simple removal. In certain embodiments, the sacrificialmaterial may be light sensitive, heat sensitive, soluble, and/or pHsensitive, etc.

In any of the processes described herein for producing a sharp tip atthe distal end of a fine sensor wire, including but not limited to thoseprocesses described in the foregoing paragraphs, the sensor wire may beembedded in a sacrificial material prior to any steps of removingmaterial of the wire (such as grinding, laser cutting, etc.). Thesacrificial material may increase the strength of the wire material andthereby enhance the efficacy of the material removal process by reducingthe likelihood that the wire will break during the material removalprocess. Examples of sacrificial materials suited for use in the processof FIG. 60 include, without limitation, sugar, salts, degradablepolymers, and waxes.

After the sacrificial material 1328 is applied to the sharp distal tip1326 of the sensor 1322, the membrane 1330 is applied to the sensor1322. Use of the sacrificial material allows for simplified applicationof the membrane, such that the membrane 1330 during the applicationprocess may cover not only the sensor body 1324 but also the distal tip1326. The distal tip 1326 can then be treated to break down and/orremove the sacrificial layer and thereby facilitate removal of themembrane 1330 from the sharp distal tip 1326 without damaging the tip1326. The type of post-membrane application treatment depends upon thetype of sacrificial material(s) used, but may comprise, for example, andwithout limitation, applying light, heat, a solvent, and/or combinationsthereof.

In another process, the membrane may be applied to the sensor, includingover the sharpened distal tip, without any sacrificial material. Theportion of the membrane applied to the distal tip may subsequently beheated until it softens enough such that it can be removed, for example,mechanically by scraping. For example, the softening step may comprisemelting the membrane.

FIGS. 61 and 62 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. The sensor 1332 includes a sensor body 1334 with a sharpdistal tip 1336. In a typical dipping process for applying a membrane1338, the sensor 1332 is dipped vertically with the distal tip 1336pointed downward, as shown in FIG. 61. If the membrane solution 1338 isallowed to dry with the distal tip 1336 pointed downward, gravity willpull the membrane 1338 solution downward, causing a bead to form. Thebead dulls the distal tip 1336, rendering it less effective for piercingskin and/or tissue.

The process corresponding to FIG. 62 solves this problem by usinggravity to lessen the likelihood of a bead forming. With reference toFIG. 62, the sensor 1332 is inverted, such that the sharp tip 1336points upward, after dipping in the membrane solution 1338 and beforethe solution dries. In this orientation, gravity pulls the membranesolution 1338 away from the tip 1336, thereby reducing the likelihood ofa bead forming. Instead, the membrane 1338 is more evenly distributedover the distal end of the sensor 1332, preserving the sharp distal tip1336, as shown in FIG. 62. In an alternative process, the sensor 1332may be rotated about an axis perpendicular to a longitudinal axis of thesensor 1332 while the membrane solution 1338 dries, allowing centripetalforce to pull the membrane 1338 away from the tip 1336. In the processof rotating the sensor 1332, the sensor 1332 may be orientedhorizontally, for example.

FIG. 63 illustrates another process for making a sensor configured fordirect press insertion according to the present embodiments. The sensor1340 includes a sensor body 1342 with a sharp distal tip 1344. Whendipping the sensor 1340 in a membrane solution 1346, the sensor 1340 isinverted, such that the sharp tip 1344 points upward. The sensor 1340 isonly partially submerged, such that the membrane solution 1346 nevercontacts the sharp tip 1344. The sensor 1340 is subsequently removedfrom the membrane solution 1346 and allowed to dry. Because the membranesolution 1346 never contacts the sharp tip 1344, the sharpness of thetip 1344 is preserved.

FIG. 64 illustrates another process for making a sensor configured fordirect press insertion according to the present embodiments. The sensor1348 includes a sensor body 1350 with a sharp distal tip 1352. Justproximal of the tip 1352, an annular channel 1354 or depression isformed on the sensor body 1350. In some embodiments, a band of materialis removed from the sensor 1348 to form the annular channel 1354 ordepression. However, in other embodiments, the annular channel 1354 ordepression may be formed by any of a variety of processes employed toalter the shape of a wire, such as, but not limited to, etching,skiving, grinding, or stamping. A distal end of the channel 1354 definesan edge 1356. When the sensor 1348 is subsequently dipped in a membranesolution, the edge 1356 causes the liquid meniscus of the membranesolution to break off, thereby leaving the tip 1352 of the sensor 1348uncovered by the membrane 1360. Advantageously, the membrane 1360 doesnot blunt the sharp tip 1352.

One aspect of the present embodiments includes the realization thatforming a sharp distal tip on a sensor presents challenges, such ascontaminating the membrane surface and/or damaging the membrane so thatit cannot perform its proper function. Contamination of the membrane canalter membrane properties such as diffusion. For example, a contaminantmay reduce the permeability characteristics (e.g., permselectivity) ofthe membrane. Damage to the membrane can also affect the functionalityof the sensor. For example, if membrane removal extends beyond thedistal tip to a portion intended to cover the electroactive surface thatforms an electrode, the sensor can become defective, as diffusionproperties of the sensor become substantially altered and uncontrolled.On the other hand, if excess membrane material is present at the distaltip of the sensor, the distal tip of the sensor may become dull, suchthat it becomes less effective for piercing skin and/or tissue. Some ofthe present embodiments provide solutions to these problems, includinghow to form a sharp distal tip by removing material from the tip and howto form a sharp distal tip by adding material to the tip.

FIGS. 65-67 illustrate another process for making a sensor configuredfor direct press insertion according to the present embodiments. Withreference to FIG. 65, the sensor 1362 includes a sensor body 1364comprising a core 1366 and an outer layer 1368. The core 1366 maycomprise, for example and without limitation, tantalum or any othermaterial. The outer layer 1368 may comprise, for example and withoutlimitation, platinum or any other material.

A first portion or band 1370 and a second portion or band 1372 of theouter layer 1368 are removed to expose the core 1366. The first band1370 of removed material is located at the distal tip 1374 of the sensorbody 1364, and the second band 1372 is located proximal of the distaltip 1374. The first and second bands 1370, 1372 may be removed using anyprocess, such as skiving, etching, grinding, stamping, or any otherprocesses. A portion of the core 1366 is also removed at the tip 1374 toform the sharp distal tip 1374. The core 1366 material may be removedusing any process.

With reference to FIG. 66, a cap 1376 is attached over the distal tip1374 of the sensor 1362. The attached cap 1376 includes a sharp distalend, and extends over a portion of the exposed core 1366, leaving aportion 1378 of the core 1366 proximal of the cap 1376 exposed. The cap1376 may comprise an absorbable material such that the cap 1376dissolves and/or is absorbed into the body of the host after the sensor1362 is inserted into the host's skin and/or tissue. The material of thecap 1376 may comprise a dissolving polymer, such as, without limitation,degradable polymers including polyvinyl-pyrrolidone (PVP), polymerizedsugar such as caramel, polyvinyl acetate, polyethylene glycol,polyesters, polyaminoacid, polycarbonate, polyanhydride, polylacticacid, polyglycolic acid, polydioxanone, polyhydroxybutyrate,polyhydroxyvalerate, polycaprolactone, polyanhydrides (e.g., aliphaticpolyanhydrides in the back bone or side chains or aromaticpolyanhydrides with benzene in the side chain), polyorthoesters,polyaminoacids (e.g., poly-L-lysine, polyglutamic acid),pseudo-polyaminoacids (e.g., with back bone of polyaminoacids altered),polycyanocrylates, polyphosphazenes, and combinations or copolymersthereof and other similar polymers.

FIG. 67 illustrates an alternative configuration for the cap 1376′ inwhich the cap 1376′ extends farther proximally along the sensor 1362.For example, the cap 1376′ may extend far enough proximally to cover atleast a portion of the outer layer 1368 proximal of the area where thesecond band 1372 of the outer layer 1368 was removed.

In some embodiments, the elongated body (e.g., wire), precursor toindividual workpieces that correspond to individual sensor pieces, isexposed to an agent that inactivates catalytic sites (e.g., enzymaticdomains). The inactivating agent may be in any of a variety of forms,such as liquid or vapor. For example, in the process corresponding toFIG. 68, wire stock 1380 is exposed to vapor 1382 (e.g., cyanoacrylate)during singulation (i.e., the process of cutting wire stock intoindividual workpieces corresponding to sensor pieces). The vapor 1382inactivates the catalytic sites at the sensor tip, thereby solving theproblem of an elevated baseline signal from exposed metal at the tip.The process of FIG. 68 is advantageously well suited for, but does notrequire, reel-to-reel continuous processing.

Various processes are contemplated for producing a sharp tip at thedistal end of a fine sensor wire. For example, the distal end of thesensor wire may be ground, or laser cut/laser ablated, or milled, orthermoformed (particularly for plastic materials), or processedaccording to any other technique(s) that can be used to shape the distaltip. The various processes for producing a sharp tip may produce avariety of tip shapes, such as, without limitation, beveled (similar toa hypodermic needle profile), cone shaped (similar to a pencil tip), orstepped (similar to an acupuncture needle).

FIG. 69 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. In theprocess corresponding to FIG. 69, a distal end 1384 of a sensor wire1386 is dipped in a chemical 1388 to remove material from the end of thewire 1386 and form a pointed tip 1390. The chemical 1388 into which thewire 1386 is dipped may be, for example, an etchant, such as an acid, ora polishing solution. In an alternative embodiment, the material may beremoved from the end of the wire 1386 via electropolishing. In furtherembodiments, the material may be removed mechanically, for example, bymechanical scraping or mechanical polishing. Referring back to FIG. 69,the process illustrated therein may be advantageous for forming a tip ona very fine flexible wire where more traditional processes for forming asharp tip, such as grinding, may not work well.

FIG. 70 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. In theprocess of FIG. 70, a distal end 1392 of a sensor wire 1394 is draggedacross an abrasive surface 1396 with the sensor wire 1394 held at anangle Θ between 0° and 90° relative to the abrasive surface 1396. Forexample, Θ may be from about 15° to about 55°, sometimes from about 15°to about 30°, and other times from about 30° to about 45°, or any otherappropriate angle. The wire 1394 may be held within a support fixture(not shown) as it is moved relative to the abrasive surface 1396.Alternatively, the wire 1394 may be held still and the abrasive surface1396 may be moved relative to the wire 1394. The process of FIG. 70 may,for example, produce a wedge-shaped tip 1398 having a single flat bevel1400 on the distal end 1392 of the wire 1394. The wedge-shaped tip 1398may be simpler and/or less expensive to produce than a multifaceted(e.g. pyramidal) or conical point.

In the process of FIG. 70, a support fixture for holding the wire 1394may comprise a block having a small hole for receiving the wire 1394,with a longitudinal axis of the hole being oriented at the angle Θrelative to the abrasive surface 1396. In another alternative, the wire1394 may be held between two flat blocks cut at the angle Θ relative tothe abrasive surface 1396.

FIG. 71 corresponds to another process for making a sensor configuredfor direct press insertion according to the present embodiments. In FIG.71, a sensor wire 1402 includes an inner core 1404 and an outer layer1406. The inner core 1404 has a very small diameter, such as, forexample, less than about 400 μm, less than about 200 μm, or less thanabout 100 μm. In the process of FIG. 71, a portion of the outer layer1406 at the distal end of the sensor wire 1402 is removed from the innercore 1404 to expose a short length 1408 of the inner core 1404 at thedistal end only. The exposed length 1408 of the inner core 1404 has asufficiently small diameter that it can penetrate skin and/or tissue.The exposed portion 1408 of the inner core 1404 is preferably longenough to penetrate the host to a desired depth, but preferably as shortas possible to achieve the desired depth so that the outer layer 1406provides support to the exposed portion 1408 of the inner core 1404 toincrease the column strength of the exposed portion 1408. The outerlayer 1406 may be removed from the inner core 1404 using any process,such as mechanical stripping, laser ablation, bead blasting, abrasion,chemical etching, or any other process.

Some of the present processes for forming a sensor wire form a sharpdistal tip by adding material to the sensor wire. For example, FIGS. 72and 73 illustrate another process for making a sensor configured fordirect press insertion according to the present embodiments. Withreference to FIG. 72, the sensor wire 1410 is dipped in a bath of apolymer material 1412. The polymer material 1412 may comprise, forexample and without limitation, conductive polymer, polyelectrolyte,zwitterionic polymers, etc. After removing the sensor from the bath, avoltage is applied across the polymer material 1412, as shown in FIG.73. The voltage causes the polymer material 1412 to elongate and form asharp tip 1414.

For example, the process of FIGS. 72 and 73 may compriseelectrospinning. In electrospinning, when a sufficiently high voltage isapplied to a liquid droplet, the body of the liquid becomes charged, andelectrostatic repulsion counteracts the surface tension and the dropletis stretched. At a critical point, a stream of liquid erupts from thesurface. This point of eruption is known as the Taylor cone. If themolecular cohesion of the liquid is sufficiently high, stream breakupdoes not occur (if it does, droplets are electrosprayed) and a chargedliquid jet is formed. As the jet dries in flight, the mode of currentflow changes from ohmic to convective as the charge migrates to thesurface of the fiber. The jet is then elongated by a whipping processcaused by electrostatic repulsion initiated at small bends in the fiber,until it is finally deposited on the grounded collector. The elongationand thinning of the fiber resulting from this bending instability leadsto the formation of uniform fibers with nanometer-scale diameters.

FIGS. 74 and 75 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. With reference to FIG. 74, a sensor wire 1416 is dipped ina bath 1418 of molten polymers, or a mixture of reactivemonomer/oligomer, or dissolved polymers, or a polymer mixture. Withreference to FIG. 75, dipping the sensor wire 1416 produces a dipcoating 1420 on the portion of the sensor wire 1416 that is submerged inthe bath 1418. With reference to FIG. 75, the wire 1416 is withdrawnfrom the bath 1418, and as the wire 1416 withdraws the dip coating 1420cures to create a sharp tip 1422 on the sensor wire 1416. The withdrawalspeed and angle can be controlled such that the tip conforms to thedesired shape and sharpness. The tip can then be cooled to harden, driedto solidify, or cured by exposure to external radiation, moisture,and/or light. In some embodiments, after the wire 1416 is withdrawn fromthe bath 1418 of molten polymers, the tip 1422 is placed into a mold toproduce the sharp tip 1422.

FIG. 76 illustrates another process for making a sensor configured fordirect press insertion according to the present embodiments. In theprocess of FIG. 76, a sensor wire 1424 includes a sensor body 1426 and amembrane 1428 covering at least a portion of the sensor body 1426. Ahard and sharp tip 1430 is secured to the membrane-covered sensor wire1424. For example, the tip 1430 may be cast onto the wire 1424 using amold 1432. If the tip 1430 is a moldable material, such as athermoplastic, the tip 1430 may be injection molded or insert molded tosecure it to the sensor body 1426. Other curable materials, such astwo-part polyurethane, can be used in a low temperature liquid injectionmolding process (LIM) to avoid exposing the membrane to a hightemperature.

In any of the embodiments described herein, the distal tip of the sensorworkpiece may be shaped via press molding. For example, in theembodiment illustrated in FIG. 76A, the sensor workpiece 1431 is firstintroduced into a station for press molding. Shaping elements 1433 arethen moved from an expanded position (FIG. 76A) into a contractedposition (FIG. 76B), whereby the distal end of the workpiece 1431 ismolded into a desired shape. FIG. 76B illustrates a cross-section of aportion of the sensor workpiece 1431 that is being shaped by the shapingelements 1433 and more proximal than the portion illustrated in FIG.76C, which in turn is more proximal than the distal tip illustrated inFIG. 76D, which has a cross-section with an area that is almost zero andthus forms a sharp tip. In the embodiment shown in FIGS. 76A-76D, thereare two shaping elements 1433, which shape the distal end of theworkpiece 1431 into a conical shape with a circular cross-section.However, in other embodiments, there may be any number of shapingelements, such as, for example, three, four, five, nine, ten, or more.In addition, the shaping elements 1433 may be configured to shape thedistal end into any variety of shapes, for example, triangular,rectangular, square, pentagon, or hexagon.

FIGS. 77 and 78 illustrate another process for making a sensorconfigured for direct press insertion according to the presentembodiments. FIG. 77 is a top plan view, and FIG. 78 is a side elevationview. With reference to FIGS. 77 and 78, the process includes a planar,flexible printed circuit board (PCB) 1434 embedded in an outer core1436. In the illustrated embodiment, the outer core 1436 issubstantially cylindrical and includes a conical distal tip 1438configured for piercing skin and/or tissue. However, the illustratedshape is just one example and is not limiting. The outer core 1436 maycomprise any material, such as a polymer.

In the process of FIGS. 77 and 78, a section of the outer core 1436proximal of the conical tip 1438 is removed, creating a window 1440. Forexample, the outer core 1436 section may be removed via laser ablation,or any other process described herein or elsewhere for removing materialfrom a workpiece. In one example, an outer surface of the PCB 534includes a platinum layer, which resists laser ablation. Thus, when theouter core 1436 section is removed via laser ablation, the portion ofthe PCB 1434 that lies beneath the window 1440 remains intact. Thesensor 1442 is subsequently dipped in a membrane solution. The membrane1444 covers the exposed platinum surface of the PCB 1434 within thewindow 1440, and this surface defines a working electrode in thefinished sensor 1442.

FIG. 79 illustrates another process for making a sensor configured fordirect press insertion according to the present embodiments. The sensor1446 includes a sensor body 1448 having a blunt distal end 1450. Apiercing tip 1452 is positioned over the distal end 1450. The tip 1452includes an open proximal end 1454 that receives the distal end 1450 ofthe sensor body 1448. The proximal end 1454 of the piercing tip 1452 isthen crimped to secure the tip 1452 to the sensor body 1448. In someembodiments, the membrane is applied before the sensor body 1448 iscrimped to the tip 1422. In other embodiments, the membrane is appliedafter the sensor body 1448 is crimped to the tip 1422. In a furtherembodiment, the sensor 1446 is dipped upside down (i.e., with the tip1422 on top) such that the solution never contacts the tip. This processavoids the possibility of the membrane getting onto (and dulling) thetip.

In another embodiment, a piercing tip may be overmolded on the distalend of the sensor body. The overmolded tip may comprise, for example andwithout limitations, a rigid polymer such as a two-part polyurethane.The rigid tip may be overmolded on the distal end of the sensor bodyafter the membrane has been applied to the sensor body.

Another aspect of the present embodiments includes the realization thatit can be difficult to form three electrodes on an analyte sensor. Forexample, adding a third layer to a sensor wire adds significantcomplexity to the wire manufacturing process and makes it very difficultto achieve concentricity of all layers. If all layers are notconcentric, further processing steps, such as skiving, can be difficultto perform with the desired precision. Further, the tip of the sensorcan reduce sensor accuracy if conductive material and/or enzyme(s) atthe tip are exposed to the environment. Some of the present embodimentsprovide solutions to these problems.

For example, FIGS. 80 and 81 illustrate another process for making asensor configured for direct press insertion according to the presentembodiments. With reference to FIG. 80, the sensor 1456 includes a thin,flat microelectromechanical systems (MEMS) substrate 1458. For example,the MEMS substrate 1458 may be fabricated using photolithography,etching, and/or other MEMS processes.

A distal end of the substrate includes a tapered piercing tip 1460. Anelectroactive surface, or electrode, 1457 is printed on the MEMSsubstrate 1458. A conductive trace 1459 provides electrical connectionbetween the electrode 1457 and electrical contacts (not shown) of thesensor 1456. With reference to FIG. 81, the substrate 1458 is coatedwith a membrane 1462. For example, the membrane coating 1462 may beapplied with a dip coat process to obtain a conformal coating. In theillustrated embodiment, the membrane coating 1462 is substantiallycylindrical and covers the piercing tip 1460 of the substrate 1458.

The process illustrated in FIGS. 80 and 81 advantageously leverages thebenefits of both MEMS processing and dip coating to obtain a cylindricaldirect press insertion sensor having three electrodes. Using MEMStechnology, all three electrodes can be easily fabricated on the flat,flexible substrate 1458. For example, the working electrode (andpossibly other electrodes) may be on top and bottom surfaces of thesubstrate 1458 for averaging. The substrate 1458 with electrodes issubsequently dipped into a hard membrane solution to obtain thecylindrical membrane coating 1462. The membrane 1462 may be, forexample, a shape memory material and/or a heat/hydration softeningmaterial. While the membrane coating 1462 need not be cylindrical, acylindrical membrane coating advantageously enables radial diffusion ofthe analyte, which is beneficial, because radial diffusion facilitatesfaster mass transport, leading to shortened response times to achievesteady state. Further, the MEMS substrate 1458 can be inert, therebyeliminating the issue of tip robustness.

One aspect of the present embodiments includes the realization that apiercing tip can be formed on sensors during a step of singulating asensor wire into individual sensors. For example, singulating processesmay include, without limitation, mechanical pressing, hot pressing,laser ablation, extruding, milling, etc. By forming a piercing tipduring singulation, a sharp distal tip can be formed prior to applyingthe membrane to the sensor, thereby avoiding cross-contamination anddamaging the delicate membrane with a subsequent tip-forming step.

For example, FIG. 82 illustrates another process for making a sensorconfigured for direct press insertion according to the presentembodiments. Forming a sensor tip configured for piercing skin and/ortissue is difficult with certain materials. Typical processes likegrinding are not suitable for materials like aluminum, tantalum, etc.FIG. 82 illustrates an alternative process in which the sensor is pulledto form a sharp tip.

In general, when an elongate piece of material is placed in tensionalong its longitudinal axis and pulled past its elastic limit, it beginsto plastically deform. Depending on the material's properties, thematerial may “neck.” Necking is the localized concentration of strainthat occurs as the cross sectional area of the material increases andthe stress at the reduced cross section simultaneously increases.Necking rapidly increases the rate of deformation at the area of reducedcross section. From the point where necking occurs, future deformationis concentrated in the necking area. In practice, for a sample having acircular cross section, necking produces a localized reduction indiameter. Eventually, the sample fails at or near the center of thenecked section. This failure leaves two “half necks,” each of whichincludes a sharp point that can be used to form a piercing tip for asensor.

According to the above process, and with reference to FIG. 82, a sensorwire 1470 is placed in tension along its longitudinal axis A_(L). Thesensor wire 1470 necks in an intermediate region 1472. After failureoccurs, two sensors having sharp piercing tips are formed. Furtherprocessing may be performed on the piercing tips, such as burr removal,polishing, further sharpening, etc.

In one alternative, as shown in FIG. 83, a portion of the sensor wire1470 may be heated before and/or during the process of applying tension.For example, heat may be applied with a resistive heating element 1474,a flame, or any other heat source. The applied heat softens the wirematerial, making it more likely that necking and failure will occur inthe heated region 1476.

Also in one alternative, after tension is applied to the sensor wire andnecking begins to occur, but prior to failure, the tension may bereleased and the two portions of the sensor wire on either side of thenecked region may be separated by any process, such as shearing,cutting, laser ablation, etc.

FIGS. 84-86 illustrate another process for making a sensor configuredfor direct press insertion according to the present embodiments. Withreference to FIG. 84, a sensor wire 1478 is positioned between opposingcutting blades 1480. The cutting blades 1480 singulate the sensor wire1478 into smaller pieces, each of which is subsequently processed toproduce a sensor. FIG. 84 illustrates a first embodiment of the cuttingblades 1480 in solid lines, and a second embodiment of the cuttingblades 1480′ in dashed lines. In the solid line embodiment 1480, eachblade 1480 includes a cutting edge defined by converging surfaces 1482that lie at a first angle Φ₁ to one another. In the dashed lineembodiment, each blade 1480′ includes a cutting edge defined byconverging surfaces 1484 that lie at a second angle Φ₂ to one another,where Φ₂>Φ₁. FIG. 85 illustrates the shape of the cut 1486 made in thesensor wire 1478 by the blades 1480 of the solid line embodiment, andFIG. 86 illustrates the shape of the cut 1486′ made in the sensor wire1478′ by the blades 1480′ of the dashed line embodiment. Because Φ₂>Φ₁,the cut 1486′ made in the sensor wire 1478′ by the blades 1480′ of thedashed line embodiment results in a smaller angle φ₂ defined between theconverging surfaces at the piercing tips 1488′ of the sensors 1490′ inFIG. 86 as compared to the angle φ₁ defined between the convergingsurfaces at the piercing tips 1488 of the sensor wires 1490 in FIG. 85.The smaller angle φ₂ advantageously creates a sharper point on thesensor wires 1490′ in FIG. 86 as compared to the sensor wires 1490 inFIG. 85. Thus, by using the blades 1480′ of the dashed line embodimentin FIG. 84, sharper piercing tips may be produced.

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Methods and devices that are suitable for use in conjunction withaspects of the preferred embodiments are disclosed in U.S. applicationSer. No. 09/447,227 filed on Nov. 22, 1999 and entitled “DEVICE ANDMETHOD FOR DETERMINING ANALYTE LEVELS”; U.S. application Ser. No.12/828,967 filed on Jul. 1, 2010 and entitled “HOUSING FOR ANINTRAVASCULAR SENSOR”; U.S. application Ser. No. 13/461,625 filed on May1, 2012 and entitled “DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTESENSOR”; U.S. application Ser. No. 13/594,602 filed on Aug. 24, 2012 andentitled “POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS”; U.S.application Ser. No. 13/594,734 filed on Aug. 24, 2012 and entitled“POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS”; U.S. applicationSer. No. 13/607,162 filed on Sep. 7, 2012 and entitled “SYSTEM ANDMETHODS FOR PROCESSING ANALYTE SENSOR DATA FOR SENSOR CALIBRATION”; U.S.application Ser. No. 13/624,727 filed on Sep. 21, 2012 and entitled“SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA”; U.S.application Ser. No. 13/624,808 filed on Sep. 21, 2012 and entitled“SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA”; U.S.application Ser. No. 13/624,812 filed on Sep. 21, 2012 and entitled“SYSTEMS AND METHODS FOR PROCESSING AND TRANSMITTING SENSOR DATA”; U.S.application Ser. No. 13/732,848 filed on Jan. 2, 2013 and entitled“ANALYTE SENSORS HAVING A SIGNAL-TO-NOISE RATIO SUBSTANTIALLY UNAFFECTEDBY NON-CONSTANT NOISE”; U.S. application Ser. No. 13/733,742 filed onJan. 3, 2013 and entitled “END OF LIFE DETECTION FOR ANALYTE SENSORS”;U.S. application Ser. No. 13/733,810 filed on Jan. 3, 2013 and entitled“OUTLIER DETECTION FOR ANALYTE SENSORS”; U.S. application Ser. No.13/742,178 filed on Jan. 15, 2013 and entitled “SYSTEMS AND METHODS FORPROCESSING SENSOR DATA”; U.S. application Ser. No. 13/742,694 filed onJan. 16, 2013 and entitled “SYSTEMS AND METHODS FOR PROVIDING SENSITIVEAND SPECIFIC ALARMS”; U.S. application Ser. No. 13/742,841 filed on Jan.16, 2013 and entitled “SYSTEMS AND METHODS FOR DYNAMICALLY ANDINTELLIGENTLY MONITORING A HOST'S GLYCEMIC CONDITION AFTER AN ALERT ISTRIGGERED”; and U.S. application Ser. No. 13/747,746 filed on Jan. 23,2013 and entitled “DEVICES, SYSTEMS, AND METHODS TO COMPENSATE FOREFFECTS OF TEMPERATURE ON IMPLANTABLE SENSORS”.

The above description presents the best mode contemplated for carryingout the present invention, and of the manner and process of making andusing it, in such full, clear, concise, and exact terms as to enable anyperson skilled in the art to which it pertains to make and use thisinvention. This invention is, however, susceptible to modifications andalternate constructions from that discussed above that are fullyequivalent. Consequently, this invention is not limited to theparticular embodiments disclosed. On the contrary, this invention coversall modifications and alternate constructions coming within the spiritand scope of the invention as generally expressed by the followingclaims, which particularly point out and distinctly claim the subjectmatter of the invention. While the disclosure has been illustrated anddescribed in detail in the drawings and foregoing description, suchillustration and description are to be considered illustrative orexemplary and not restrictive.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art, and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated. Terms and phrasesused in this application, and variations thereof, especially in theappended claims, unless otherwise expressly stated, should be construedas open ended as opposed to limiting. As examples of the foregoing, theterm ‘including’ should be read to mean ‘including, without limitation,’including but not limited to,′ or the like; the term ‘comprising’ asused herein is synonymous with ‘including,’ containing,′ or‘characterized by,’ and is inclusive or open-ended and does not excludeadditional, unrecited elements or method steps; the term ‘having’ shouldbe interpreted as ‘having at least;’ the term ‘includes’ should beinterpreted as ‘includes but is not limited to;’ the term ‘example’ isused to provide exemplary instances of the item in discussion, not anexhaustive or limiting list thereof; adjectives such as ‘known’,‘normal’, ‘standard’, and terms of similar meaning should not beconstrued as limiting the item described to a given time period or to anitem available as of a given time, but instead should be read toencompass known, normal, or standard technologies that may be availableor known now or at any time in the future; and use of terms like‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment of the invention. Likewise, a group of itemslinked with the conjunction ‘and’ should not be read as requiring thateach and every one of those items be present in the grouping, but rathershould be read as ‘and/or’ unless expressly stated otherwise. Similarly,a group of items linked with the conjunction ‘or’ should not be read asrequiring mutual exclusivity among that group, but rather should be readas ‘and/or’ unless expressly stated otherwise.

Where a range of values is provided, it is understood that the upper andlower limit, and each intervening value between the upper and lowerlimit of the range is encompassed within the embodiments.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for sakeof clarity. The indefinite article ‘a’ or ‘an’ does not exclude aplurality. A single processor or other unit may fulfill the functions ofseveral items recited in the claims. The mere fact that certain measuresare recited in mutually different dependent claims does not indicatethat a combination of these measures cannot be used to advantage. Anyreference signs in the claims should not be construed as limiting thescope.

It will be further understood by those within the art that if a specificnumber of an introduced claim recitation is intended, such an intentwill be explicitly recited in the claim, and in the absence of suchrecitation no such intent is present. For example, as an aid tounderstanding, the following appended claims may contain usage of theintroductory phrases ‘at least one’ and ‘one or more’ to introduce claimrecitations. However, the use of such phrases should not be construed toimply that the introduction of a claim recitation by the indefinitearticles ‘a’ or ‘an’ limits any particular claim containing suchintroduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases‘one or more’ or ‘at least one’ and indefinite articles such as ‘a’ or‘an’ (e.g., ‘a’ and/or ‘an’ should typically be interpreted to mean ‘atleast one’ or ‘one or more’); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of ‘two recitations,’ without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to ‘at least one of A, B, and C, etc.’ is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., ‘a system having at least one ofA, B, and C’ would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to ‘at least one of A, B, or C, etc.’ is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., ‘a system having at leastone of A, B, or C’ would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase ‘A or B’ will be understood toinclude the possibilities of ‘A’ or ‘B’ or ‘A and B.’

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

1. A sensor device for measuring an analyte concentration in a host, thesensor device being configured for implantation in the host without useof an inserter, comprising: a sensor unit comprising a sensor body, atleast one electrode, and a membrane covering at least a portion of theat least one electrode; a piercing element at a distal end of the sensorunit, the piercing element being configured for piercing skin and/ortissue of the host; and a mounting unit spaced from the sensor tip andconfigured to support the sensor device on an exterior surface of thehost's skin; wherein the sensor body comprises a stimulus-responsivematerial that changes at least one material property responsive to astimulus.
 2. The sensor device of claim 1, wherein the at least onematerial property is at least one of hardness, shape, permeability,relative hydrophilicity, modulus of elasticity, or conformation ofpolymer orientation.
 3. The sensor device of claim 2, wherein the sensorbody is hard ex vivo and soft in vivo.
 4. The sensor device of claim 1,wherein the stimulus that induces the change in the at least onematerial property is at least one of temperature, hydration, radiation,electrical stimulus, or a magnetic field.
 5. The sensor device of claim1, wherein the sensor body is a polymer
 6. The sensor device of claim 5,wherein the sensor body is polyurethane, polyester, polyamide,polyacrylate, or polyether, or copolymers thereof.
 7. The sensor deviceof claim 1, wherein the stimulus-responsive material is a shape memorymetal.
 8. (canceled)
 9. The sensor device of claim 1, wherein the sensorbody defines a first shape prior to insertion into the host's skin. 10.The sensor device of claim 9, wherein the sensor body defines amemorized shape, and the sensor body returns to the memorized shapeafter insertion into the host's skin.
 11. The sensor device of claim 10,wherein the first shape is curved or straight, and the memorized shapeis curved or straight.
 12. The sensor device of claim 10, wherein whenthe sensor body returns to the memorized shape stored spring energy isreleased from the sensor body.
 13. The sensor device of claim 12,wherein the released spring energy creates a whipping action thatfacilitates piercing the host's skin.
 14. A method of making a sensordevice configured for implantation in a host without use of an inserter,the method comprising: forming a piercing tip on a sensor unit, thesensor unit including a sensor body, at least one electrode, and amembrane covering at least a portion of the at least one electrode;wherein the membrane is applied to the sensor unit prior to forming thepiercing tip on the sensor unit.
 15. The method of claim 14, furthercomprising applying the membrane to the sensor unit.
 16. The method ofclaim 14, wherein forming the piercing tip comprises forming an annularchannel about a circumference of a wire that is coated with themembrane.
 17. The method of claim 16, wherein the annular channelextends through the membrane and partially into the wire
 18. The methodof claim 16, further comprising applying tension to the coated wire. 19.The method of claim 18, wherein the tension induces strain in the wireproximate the annular channel, causing the wire to neck and fracture.20. The method of claim 19, wherein the necking forms the piercing tipon the sensor body.
 21. The method of claim 20, further comprisingcovering the piercing tip with a protective outer layer.